Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines

ABSTRACT

The invention relates to novel phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and PI3k-related kinase (PIKKs) inhibitor compounds of formula (I), 
                         
wherein X 1 , X 2  and X 3  are N or CH, with the proviso that at least two of X 1 , X 2  and X 3  are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

FIELD OF THE INVENTION

The invention relates to new difluoromethyl-aminopyridyl- anddifluoromethyl-aminopyrimidinyl-substituted triazines and pyrimidines astherapeutic agents and diagnostic probes useful for modulating cellularactivities such as signal transduction, proliferation, differentiation,cell death, migration, and control, release and action of inflammatorymediators, chemokines and cytokines. The compounds of the inventionmodulate kinase activities, in particular those of phosphoinositide3-kinase (PI3K), phosphoinositide 4-kinase (PI4K), mammalian target ofrapamycin (mTOR), Vps34 and PI3K-related kinases (PIKKs).

BACKGROUND OF THE INVENTION

Protein kinases participate in the signaling events and control cellularactivation, growth, differentiation, survival and migration in responseto extracellular mediators or stimuli including growth factors,cytokines or chemokines. In general, these kinases are classified in twogroups, those that preferentially phosphorylate tyrosine residues andthose that preferentially phosphorylate serine and/or threonineresidues. Tyrosine kinases include membrane-spanning growth factorreceptors, for example the epidermal growth factor receptor (EGFR) andcytosolic non-receptor kinases including Src family kinases, the Sykfamily kinases and the Tec family kinases.

Increased protein kinase activities are involved in many diseasesincluding cancer, metabolic diseases, immunological diseases andinflammatory disorders. These can be caused either directly orindirectly by the failure of control mechanisms due to mutation(s),overexpression or inappropriate control of enzyme activity.

Protein tyrosine kinases—both receptor tyrosine kinases and non-receptorkinases—are essential for the activation and proliferation of cells ofthe immune system. Among the earliest detectable events uponimmunoreceptor activation in mast cells, T cells and B cells is thestimulation of non-receptor tyrosine kinases.

Phosphoinositide 3-kinases (PI3Ks) were early on identified as lipidkinases associated with viral oncogenes [Whitman et al., Nature315:239-242 (1985)], and for the last 20 years, the connection betweencancer and PI3K has been further substantiated [Wymann et al., Curr.Opin. Cell Biol. 17:141-149 (2005)]. PI3Ks have since been recognized tomodulate a wide range of cellular activities, and to be central to thegrowth and metabolic control. Genetically modified mice targeting thePI3K pathway, and the elucidation of human hereditary disease likeCowden's syndrome, tuberous sclerosis, ataxia telangiectasia, X-linkedmyotubular myopathy and Charcot-Marie-Tooth neuropathy, have providedfurther insight into the cellular and systemic role of phosphoinositidesignaling. Deregulation of phosphoinositide levels, and in particularthe product of class I PI3Ks, PtdIns (3,4,5)P₃, is involved in thepathogenesis of cancer, chronic inflammation, allergy, metabolicdisease, diabetes and cardiovascular problems.

PI3Ks are a family of enzymes, which phosphorylate the 3′-OH position ofthe inositol ring of phosphoinositides. They have been divided intothree classes on the basis of structural features and in vitro lipidsubstrate specificity [Marone et al., Biochimica et Biophysica Acta1784:159-185 (2008)]. Class I PI3Ks form heterodimers, which consist ofone of the four closely related catalytic subunits of approx. 110 kDa,and an associated regulatory subunit belonging to two distinct families.In vitro they are capable to convert PtdIns to PtdIns-3-P, PtdIns-4-P toPtdIns(3,4)P₂, and PtdIns(4,5)P₂ to PtdIns(3,4,5)P₃, but the in vivosubstrate is PtdIns(4,5)P₂ [Cantley et al., Science 296:1655-1657(2002)]. Class I PI3Ks are activated by a large variety of cell-surfacereceptors, comprising growth factor receptors as well as Gprotein-coupled receptors.

Class II PI3Ks are capable to phosphorylate PtdIns and PtdIns-4-P invitro, but their relevant in vivo substrates are still underinvestigation. This class of large (170-200 kDa) enzymes has threemembers, all characterized by a C-terminal C2 homology domain. Noadaptor molecules for class II PI3Ks have been identified so far. ClassIII PI3Ks are solely able to phosphorylate PtdIns, and thus generateonly PtdIns-3-P. The single member of this class is Vps34, of which theS. cerevisiae Vps34p (vacuolar protein sorting mutant 34 protein) is theprototype, and has been shown to play an essential role in traffickingof newly synthesized proteins from the Golgi to the yeast vacuole, anorganelle equivalent to lysosomes in mammals [Schu et al., Science260:88-91 (1993)].

Phosphoinositide 4-kinases (PI4Ks) phosphorylate the 4′-OH position ofthe inositol ring of PtdIns, and thereby generate PtdIns-4-P. This lipidcan then be further phosphorylated by PtdIns-4-P 5-kinases to generatePtdIns (4,5)P₂, which is the main source for phospholipase C and PI3Ksignaling at the plasma membrane. Four PI4Ks isoforms are known: PI4KIIαand β and PI4KIIIα and β. The PI4KIIIs are most closely related toPI3Ks.

The class of PI3K-related proteins, referred to as class IV PI3Ks,consists of high molecular weight enzymes with a catalytic core similarto PI3Ks and PI4Ks and include the mammalian target of rapamycin (mTOR,also known as FRAP), DNA-dependent protein kinase (DNA-PKcs), the ataxiatelangiectasia mutated gene product (ATM), ataxia telangiectasia related(ATR), SMG-1 and transformation/transcription domain-associated protein(TRRAP). The first five members are active protein serine-threoninekinases that are involved in cell growth control andgenome/transcriptome surveillance [Marone et al., Biochimica etBiophysica Acta 1784:159-185 (2008)]. DNA-PKcs, ATM, ATR and SMG-1 areinvolved in DNA damage responses. The only active kinase not involved inDNA damage is mTOR, which is regulated by growth factors and nutrientavailability, and coordinates protein synthesis, cell growth andproliferation. Target of rapamycin (mTOR) complexes 1 and 2 integrategrowth factor signaling (via PI3K/PKB and the Ras/MAPK cascade), energystatus (LKB1 and AMPK) and nutrient detection. TOR is positivelyregulated by PKB/Akt, which phosphorylates the negative regulator TSC2in the tuberous sclerosis complex (TSC), resulting in activation of theGTPase Rheb and mTOR. In parallel, mTOR stimulates translation ofribosomal proteins and therefore ribosome biogenesis via the activation[Wullschleger et al., Cell 124:471 (2006)]. Rapamycin and itsderivatives, RAD001 and CCI-779, bind to FKBP12, and the complex blocksmTOR complex 1 (mTORC1) activity very selectively. Various clinicaltrials were initiated using rapamycin and derivatives, mostly inpatients with tumors displaying elevated PI3K signaling and hyperactivemTOR.

The PI3K pathway is a key signaling transduction cascade controlling theregulation of cell growth, proliferation, survival as well as cellmigration. PI3Ks are activated by a wide variety of different stimuliincluding growth factors, inflammatory mediators, hormones,neurotransmitters, and immunoglobulins and antigens [Wymann et al.,Trends Pharmacol. Sci. 24:366-376 (2003)]. The class IA PI3K isoformsPI3Kα, β and δ are all bound to one of the p85/p55/p50 regulatorysubunits, which all harbor two SH2 domains that bind with high affinityto phosphorylated Tyr-X-X-Met motifs. These motifs are present inactivated growth factor receptors, their substrates and numerous adaptorproteins. As described above, activation of the PI3K/PKB signalingcascade has a positive effect on cell growth, survival andproliferation. Constitutive up-regulation of PI3K signaling can have adeleterious effect on cells leading to uncontrolled proliferation,enhanced migration and adhesion-independent growth. These events favornot only the formation of malignant tumors, but also the development ofinflammatory and autoimmune disease.

The patent applications WO2010/052569, WO2007/084786 and WO2008/098058describe certain analogous triazines and pyrimidines derivatives havingPI3K and mTOR inhibiting properties, and their use as pharmaceuticals.

SUMMARY OF THE INVENTION

The invention relates in a first aspect to difluoromethyl-substitutedheteroaromatic compounds of formula (I),

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N;

Y is N or CH;

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

    -   (ii) phenyl optionally substituted with 1 to 3 R⁷, wherein R⁷ is        independently at each occurrence halogen, —OH, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃        or N(CH₃)₂;

    -   (iii) a 5- to 6-membered heteroaryl ring W containing one to        four heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁸, wherein R⁸ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

    -   (iv) a saturated 4- to 6-membered heterocyclic ring Z containing        1 to 3 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

    -   (v) OR¹², wherein R¹² is C₁-C₃alkyl, C₁-C₃haloalkyl,        C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₁-C₂alkyleneC₃-C₆cycloalkyl;        Cycle-P or C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a        saturated 4- to 6-membered heterocyclic ring containing 1 to 3        heteroatoms independently selected from N, O and S, optionally        substituted by 1 to 3 R¹³, wherein R¹³ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl optionally substituted with        one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃);        Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5-        to 6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); or

    -   (vi) NR¹⁵R¹⁶; wherein R¹⁵ and R¹⁶ are independently of each        other H, C₁-C₃alkyl optionally substituted with one or two OH,        C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl; Cycle-P or        C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a saturated 4-        to 6-membered heterocyclic ring containing 1 to 3 heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹³, wherein R¹³ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); Cycle-Q or        C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5- to        6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃);

with the proviso that at least one of R¹ and R² is a morpholinyl offormula II; and prodrugs, metabolites, tautomers, solvates andpharmaceutically acceptable salts thereof.

In further aspects, the invention relates to pharmaceutical compositionscomprising a compound of formula (I) as defined hereinbefore, and tomethods of preventing or treating a disease or disorder modulated byPI3Ks, mTOR and PIKKs, in particular treating a hyperproliferativedisorder, comprising administering to a mammal in need of such treatmentan effective amount of a compound of formula (I) as definedhereinbefore. An additional aspect of the invention is the use of acompound of formula (I) as defined hereinbefore for the treatment orprevention of a disease or condition modulated by PI3Ks, mTOR and PIKKsin a mammal, and the use of a compound of formula (I) as definedhereinbefore in the preparation of a medicament for the treatment orprevention of a disease or condition modulated by PI3Ks, mTOR and PIKKs,in a mammal.

In again further aspects, the invention relates to the use of aneffective amount of compounds of formula (I) as defined hereinbefore incombination with standard treatment, such as chemotherapy, radiotherapy,targeted therapy or immunotherapy of a disease or disorder modulated byPI3Ks, mTOR and PIKKs, in particular hyperproliferative disorders.

Further the invention relates to the synthesis of compounds of formula(I) as defined hereinbefore including tautomers, solvates,intermediates, prodrugs and salts of said compounds.

Further aspects and embodiments of the present invention will be becomeapparent as this description continues.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the presented and furtheraspects and the presented and further embodiments of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated embodiments, it will be understood that they are not intendedto limit the invention to those embodiments. On the contrary, theinvention is intended to cover all alternatives, modifications, andequivalents which may be included within the scope of the presentinvention as defined by the aspects of the present invention and, inparticular the claims. One skilled in the art will recognize manymethods and materials similar or equivalent to those described herein,which could be used in the practice of the present invention. Thepresent invention is in no way limited to the methods and materialsherein described.

Definitions

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired pathological change ordisorder, such as the development or spread of cancer. For purpose ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “effective amount” means an amount of a compound of thepresent invention that (i) treats or prevents the particular disease,condition, or disorder, (ii) attenuates, ameliorates, or eliminates oneor more symptoms of the particular disease, condition, or disorder, or(iii) prevents or delays the onset of one or more symptoms of theparticular disease, condition, or disorder described herein. In the caseof cancer, the effective amount of the drug may reduce the number ofcancer cells; reduce the tumor size; inhibit (i.e., slow to some extentand preferably stop) cancer cell infiltration into peripheral organs;inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; and/or relieve tosome extent one or more of the symptoms associated with the cancer. Tothe extent the drug may prevent growth and/or kill existing cancercells, it may be cytostatic and/or cytotoxic. For cancer therapy,efficacy can be measured, for example, by assessing the time to diseaseprogression (TIP) and/or determining the response rate (RR).

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukaemia or lymphoid malignancies.More particular examples of such cancers include squamous cell cancer(e.g., epithelial squamous cell cancer), lung cancer includingsmall-cell lung cancer, non-small cell lung cancer (“NSCLC”),adenocarcinoma of the lung and squamous carcinoma of the lung, cancer ofthe peritoneum, hepatocellular cancer, gastric or stomach cancerincluding gastrointestinal cancer, pancreatic cancer, glioblastoma,cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma,breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial or uterine carcinoma, salivary gland carcinoma, kidney orrenal cancer, prostate cancer, vulval cancer, thyroid cancer, hepaticcarcinoma, anal carcinoma, penile carcinoma, bile duct cancer, mantlecell lymphoma, CNS lymphoma, chronic lymphocytic leukemia, non-Hodgkin'slymphoma, as well as head and neck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of known chemotherapeutic agents includetrastuzumab, pertuzumab, erlotinib (TARCEVA®, Genentech/Roche/OSIPharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant(FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole(FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate(VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU(5-fluorouracil), leucovorin, rapamycin (Sirolimus, RAPAMUNE®, Wyeth),lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SCH66336), sorafenib (NEXAVAR, Bayer Labs), and gefitinib (IRESSA®,AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN®cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and melamines including altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins; acamptothecin (including the synthetic analog topotecan); bryostatin;callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesinsynthetic analogs); cryptophycins; dolastatin; duocarmycin (includingthe synthetic analogs, KW-2189 and CB1-TM1); eleutherobin;pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such aschlorambucil, chlornaphazine, chlorophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such asthe enediyne antibiotics (e.g., calicheamicin, especially calicheamicingamma 1 and calicheamicin omegal 1; dynemicin, including dynemicin A;biphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores, aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, carminomycin,carzinophillin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazol-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin),morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid;triaziquone; trichothecenes; urethane; indesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb),ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulationsof paclitaxel, and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis);chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide; ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CP-11;topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);retinoids such as retinoic acid; and pharmaceutically acceptable salts;acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective receptor modulators (SERMs),including, for example, tamoxifen (including NOLVADEX®; tamoxifencitrate), raloxifene, droloxifene, and FARESTON® (toremifine citrate);(ii) aromatase inhibitors that inhibit the enzyme aromatase, whichregulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, MEGASE® (megestrol acetate); AROMASIN®(exemestane; Pfizer), formestanie, fadrazole, RIVISOR® (vorozole),FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca);(iii) anti-androgens such as flutamide, nilutamide; (iv) protein kinaseinhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Raf I and H-Ras; (vii) ribozymes such asVEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expressioninhibitors; (viii) vaccines such as gene therapy vaccines, for example,ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rII-2; a topoisomerase 1inhibitor such as LURTOTECANE®; ABARELIX® rmRH; (ix) anti-angiogenicagents such as bevacizumab (AVASTIN®, Genentech/Roche); and (x)pharmaceutically acceptable salts, acids and derivatives of any of theabove.

The term “prodrug” as used in this application refers to a precursor orderivative form of a compound of the invention that may have improvedproperties such as better solubility, reduced cytotoxicity or increasedbioavailability compared to the parent compound or drug and is capableof being activated or converted into the more active parent form. Theprodrugs of this invention include, but are not limited to, derivativesof the amino group connected to the pyridine or pyrimidine nucleus inwhich one or two hydrogens are replaced by a suitable substituent, orderivatives of the ring amino function if R² is piperazin-1-yl. Examplesof such prodrugs are compounds acylated by an amino acid selected fromthe 20 most often occurring natural L-alpha-amino acids, acylated by adipeptide such as L-Ala-L-Ala, by carbonic acid, sulfuric acid orphosphoric acid, as well as pharmaceutically acceptable salts thereof.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound. Inparticular, compounds of formula (I) as defined hereinbefore, which areoxygenated or hydroxylated at any one position in the morpholine,piperazine or thiomorpholine ring R¹ and/or R² are consideredmetabolites. Further metabolites considered are thiomorpholine S-oxidesand thiomorpholine S,S-dioxides. Accordingly, the invention is alsodirected to metabolites of compounds of the invention, includingcompounds produced by a process comprising contacting a compound of thisinvention with a mammal for a period of time sufficient to yield ametabolic product thereof.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactants, which is useful for delivery of a drug(such as the PI3K and mTOR kinase inhibitors disclosed herein and,optionally, a chemotherapeutic agent) to a mammal. The components of theliposome are commonly arranged in a bilayer formation, similar to thelipid arrangement of biological membranes.

The term “chiral” refers to molecules, which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules, which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds, which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality in which the compounds are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and chemical and biologicalreactivities. Mixtures of diastereomers may be separated under highresolution analytical procedures such as electrophoresis andchromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McRaw-Hiff Dictionary of Chemical Terms (1984),McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or l meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric or a scalemic mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or aracemate. The term “tautomer” or “tautomeric form” refers to structuralisomers of different energies, which are interconvertible via a lowenergy barrier. For example, proton tautomers include interconversionsvia migration of a proton, such as keto-enol and imine-enamineisomerizations.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention, in particular acid addition salts. Exemplary saltsinclude, but are not limited to, sulfate, citrate, acetate, oxalate,chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate,oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate,formate, benzoate, glutamate, methanesulfonate (mesylate),ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoatesalts. A pharmaceutically acceptable salt may involve the inclusion ofanother molecule such as an acetate ion, a succinate ion or othercounter ion. The counter ion may be any organic or inorganic moiety thatstabilizes the charge on the parent compound. Furthermore, apharmaceutically acceptable salt may have more than one charged atom inits structure. Instances where multiple charged atoms are part of thepharmaceutically acceptable salt can have multiple counter ions. Hence,a pharmaceutically acceptable salt can have one or more charged atomsand/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, trifluoroacetic acid, maleic acid, succinicacid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalicacid, glycolic acid, salicylic acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha hydroxy acid, such ascitric acid or tartaric acid, an amino acid, such as aspartic acid orglutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid,a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,or the like.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, aceticacid, and ethanolamine. The term “hydrate” refers to the complex wherethe solvent molecule is water.

The term “protecting group” refers to a substituent that is commonlyemployed to block or protect a particular functionality during thereaction of other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,tert-butoxycarbonyl (BOC), benzyloxycarbonyl and9-fluorenylmethylenoxycarbonyl (Fmoc). For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

The terms “compound of this invention” and “compounds of the presentinvention” and “compounds of formula (I)” include stereoisomers,geometric isomers, tautomers, solvates, pharmaceutically acceptablesalts, and solvates of the salts thereof.

The term “mammal” includes, but is not limited to, humans, mice, rats,guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. Theterm “mammal”, as used herein, preferably refers to humans.

The present invention provides new difluoromethyl-aminopyridyl- anddifluoromethyl-aminopyrimidinyl-substituted triazines and pyrimidines,and pharmaceutical formulations thereof, which are useful as therapeuticagents and novel diagnostic probes. Moreover, these compounds arepotentially useful in the treatment of diseases, conditions and/ordisorders modulated by protein kinases and lipid kinases.

More specifically, in a first aspect, the present invention provides acompound of formula (I),

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N;

Y is N or CH;

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

    -   (ii) phenyl optionally substituted with 1 to 3 R⁷, wherein R⁷ is        independently at each occurrence halogen, —OH, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃        or N(CH₃)₂;

    -   (iii) a 5- to 6-membered heteroaryl ring W containing one to        four heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁸, wherein R⁸ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

    -   (iv) a saturated 4- to 6-membered heterocyclic ring Z containing        1 to 3 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

    -   (v) OR¹², wherein R¹² is C₁-C₃alkyl, C₁-C₃haloalkyl,        C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₁-C₂alkyleneC₃-C₆cycloalkyl;        Cycle-P or C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a        saturated 4- to 6-membered heterocyclic ring containing 1 to 3        heteroatoms independently selected from N, O and S, optionally        substituted by 1 to 3 R¹³, wherein R¹³ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl optionally substituted with        one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃);        Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5-        to 6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); or

    -   (vi) NR¹⁵R¹⁶; wherein R¹⁵ and R¹⁶ are independently of each        other H, C₁-C₃alkyl optionally substituted with one or two OH,        C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl; Cycle-P or        C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a saturated 4-        to 6-membered heterocyclic ring containing 1 to 3 heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹³, wherein R¹³ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); Cycle-Q or        C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5- to        6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃);

with the proviso that at least one of R¹ and R² is a morpholinyl offormula II; and prodrugs, metabolites, tautomers, solvates andpharmaceutically acceptable salts thereof.

In another aspect, the present invention provides for a compound offormula (I),

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N;

Y is N or CH;

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

    -   (ii) phenyl optionally substituted with 1 to 3 R⁷, wherein R⁷ is        independently at each occurrence halogen, —OH, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃        or N(CH₃)₂;

    -   (iii) a 5- to 6-membered heteroaryl ring W containing one to        four heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁸, wherein R⁸ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

    -   (iv) a saturated 4- to 6-membered heterocyclic ring Z containing        1 to 3 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

    -   (v) OR¹², wherein R¹² is C₁-C₃alkyl, C₁-C₃haloalkyl,        C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₁-C₂alkyleneC₃-C₆cycloalkyl;        Cycle-P or C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a        saturated 4- to 6-membered heterocyclic ring containing 1 to 3        heteroatoms independently selected from N, O and S, optionally        substituted by 1 to 3 R¹³, wherein R¹³ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl optionally substituted with        one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃);        Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5-        to 6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); or

    -   (vi) NR¹⁵R¹⁶; wherein R¹⁵ and R¹⁶ are independently of each        other H, C₁-C₃alkyl optionally substituted with one or two OH,        C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl; Cycle-P or        C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a saturated 4-        to 6-membered heterocyclic ring containing 1 to 3 heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹³, wherein R¹³ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); Cycle-Q or        C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5- to        6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃);

with the proviso that at least one of R¹ and R² is a morpholinyl offormula II; and prodrugs, metabolites, tautomers, solvates andpharmaceutically acceptable salts thereof, and further

-   -   with the provisos that    -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In another aspect, the present invention provides for a compound offormula (I),

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N;

Y is N or CH;

R¹ and R² are independently of each other

-   -   (vii) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

    -   (viii) phenyl optionally substituted with 1 to 3 R⁷, wherein R⁷        is independently at each occurrence halogen, —OH, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃        or N(CH₃)₂;

    -   (ix) a 5- to 6-membered heteroaryl ring W containing one to four        heteroatoms independently selected from N, O and S, optionally        substituted by 1 to 3 R⁸, wherein R⁸ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl optionally substituted with        one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

    -   (x) a saturated 4- to 6-membered heterocyclic ring Z containing        1 to 3 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

    -   (xi) OR¹², wherein R¹² is C₁-C₃alkyl, C₁-C₃haloalkyl,        C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₁-C₂alkyleneC₃-C₆cycloalkyl;        Cycle-P or C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a        saturated 4- to 6-membered heterocyclic ring containing 1 to 3        heteroatoms independently selected from N, O and S, optionally        substituted by 1 to 3 R¹³, wherein R¹³ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl optionally substituted with        one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃);        Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5-        to 6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); or

    -   (xii) NR¹⁵R¹⁶; wherein R¹⁵ and R¹⁶ are independently of each        other H, C₁-C₃alkyl optionally substituted with one or two OH,        C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl; Cycle-P or        C₁-C₂alkyleneCycle-P, wherein Cycle-P represents a saturated 4-        to 6-membered heterocyclic ring containing 1 to 3 heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹³, wherein R¹³ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃); Cycle-Q or        C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5- to        6-membered heteroaryl ring containing one to four heteroatoms        independently selected from N, O and S, optionally substituted        by 1 to 3 R¹⁴, wherein R¹⁴ is independently at each occurrence        halogen, —OH, C₁-C₃alkyl optionally substituted with one or two        OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, NHCH₃ or N(CH₃);

with the proviso that at least one of R¹ and R² is a morpholinyl offormula II;

and prodrugs, metabolites, tautomers, solvates and pharmaceuticallyacceptable salts thereof, and further

-   -   with the proviso that R¹ is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl.

In another aspect, the invention provides for a compound of formula (I),

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH;

R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and

R² is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl.

In again another aspect, the present invention provides for a compoundof formula (I) as defined herein for use in a method of preventing ortreating a disease or disorder modulated by any one of PI3Ks, mTOR andPIKKs either individually or in any combination, wherein said methodcomprises administering to a mammal in need of such prevention ortreatment an effective amount of said a compound of formula (I).Preferably, said disease or disorder is a hyperproliferative disorder.

In again a further aspect, the present invention provides for a use of acompound of formula (I) as defined herein in the preparation of amedicament for the treatment or prevention of a disease or conditionmodulated by any one of PI3Ks, mTOR and PIKKs either individually or inany combination, in a mammal, preferably in a human. Preferably, saiddisease or disorder is a hyperproliferative disorder.

In again a further aspect, the present invention provides for a use of acompound of formula (I) as defined herein in the manufacture of amedicament for the treatment or prevention of a disease or conditionmodulated any one of PI3Ks, mTOR and PIKKs either individually or in anycombination, in a mammal, preferably in a human. Preferably, saiddisease or disorder is a hyperproliferative disorder.

In again another aspect, the present invention provides for a method ofpreventing or treating a disease or disorder modulated any one of PI3Ks,mTOR and PIKKs either individually or in any combination, wherein saidmethod comprises administering to a mammal in need of such prevention ortreatment an effective amount of a compound of formula (I) as definedherein.

Each alkyl moiety either alone or as part of a larger group such asalkoxy is a straight or branched chain and is preferably C₁-C₃alkyl,more preferably C₁-C₂alkyl. Examples include in particular methyl,ethyl, n-propyl and prop-2-yl (iso-propyl). Examples of an alkoxyinclude in particular methoxy, ethoxy, n-propoxy and iso-propoxy. Asdescribed herein, alkoxy may include further substitutents such ashalogen atoms leading to haloalkoxy moieties.

The term “alkoxyalkyl” refers to a R—O—R′ moiety in which the R and R′groups are alkyl groups as defined herein. Examples includemethoxymethyl, methoxyethyl, ethoxyethyl and methoxypropyl.

Each alkylene moiety is a straight or branched chain and is,particularly for example, —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—,—CH(CH₃)—CH₂—, or —CH(CH₂CH₃)—, preferably —CH₂—, —CH₂—CH₂— or—CH(CH₃)—.

Each haloalkyl moiety either alone or as part of a larger group such ashaloalkoxy is an alkyl group substituted by one or more of the same ordifferent halogen atoms. Haloalkyl moieties include for example 1 to 5halo substituents, or 1 to 3 halo substituents. Examples include inparticular fluoromethyl, difluoromethyl, trifluoromethyl,chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.

Each haloalkenyl moiety either alone or as part of a larger group suchas haloalkenyloxy is an alkenyl group substituted by one or more of thesame or different halogen atoms. Examples include, 2-difluoro-vinyl and1,2-dichloro-2-fluoro-vinyl. Haloalkenyl moieties include for example 1to 5 halo substituents, or 1 to 3 halo substituents.

Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically andpreferably in monocyclic form, and preferably contains 3 to 6 carbonatoms. Preferred examples of monocyclic cycloalkyl groups include inparticular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom, and preferably up to four heteroatoms selectedfrom nitrogen, oxygen and sulfur as ring members. Heteroaryl rings donot contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacentoxygen and sulfur atoms within the ring. Preferred examples include inparticular pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, furanyl, and thiophenyl

The term “heterocyclic ring” refers to a saturated or partiallyunsaturated carbocyclic ring containing one to three heteroatomsselected from nitrogen, oxygen and sulfur as ring members. Such rings donot contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacentoxygen and sulfur atoms within the ring. Preferred examples include inparticular tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, piperidinyl, piperazinyl, dioxanyl, morpholinyl,oxazolidinyl and isoxazolidinyl.

Where a group is said to be optionally substituted, preferably there areoptionally 1-3 substituents, more preferably optionally 1-2substituents.

Certain compounds of formula (I) may contain one or two or more centersof chirality and such compounds may be provided as pure enantiomers orpure diastereoisomers as well as mixtures thereof in any ratio. Thecompounds of the invention also include all tautomeric forms of thecompounds of formula (I).

In a preferred embodiment, the present invention provides for thecompound of formula (I) as defined herein and tautomers, solvates andpharmaceutically acceptable salts thereof. In another preferredembodiment, the present invention provides for the compound of formula(I), wherein X¹, X² and X³ are N.

In another preferred embodiment, (i) said X¹ and said X² are N, and saidX³ is CH; (ii) said X¹ and said X³ are N, and said X² is CH; or (iii)said X² and said X³ are N, and said X¹ is CH, and preferably tautomers,solvates and pharmaceutically acceptable salts thereof. In anotherembodiment, (i) said X¹ and said X² are N, and said X³ is CH; or (ii)said X² and said X³ are N, and said X¹ is CH, and preferably tautomers,solvates and pharmaceutically acceptable salts thereof. In anotherpreferred embodiment, said X¹ and said X³ are N, and said X² is CH; andpreferably tautomers, solvates and pharmaceutically acceptable saltsthereof.

In another preferred embodiment, said Y is N, and preferably tautomers,solvates and pharmaceutically acceptable salts thereof. In anotherpreferred embodiment, said Y is CH, and preferably tautomers, solvatesand pharmaceutically acceptable salts thereof.

In another preferred embodiment, said R¹ and said R² are independentlyof each other (i) a morpholinyl of formula (II); (ii) said 5- to6-membered heteroaryl ring W; (iii) said saturated 4- to 6-memberedheterocyclic ring Z; (iv) said OR¹²; or (v) said NR¹⁵R¹⁶.

In another preferred embodiment, said R¹ and said R² are independentlyof each other selected from

In another preferred embodiment, said R¹ and said R² are independentlyof each other selected from

In another preferred embodiment, R¹ and R² are independently of eachother selected from

In another preferred embodiment, R¹ and R² are independently of eachother selected from

In another preferred embodiment, said compound of formula (I) isselected from

-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   4-(difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine;-   4′-(difluoromethyl)-2,6-dimorpholino-[4,5′-bipyrimidin]-2′-amine;-   4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine;-   4′-(difluoromethyl)-4,6-dimorpholino-[2,5′-bipyrimidin]-2′-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl(pyridin-2-amine;-   2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′-(difluoromethyl)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;-   5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   4′-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5′-bipyrimidin]-2′-amine;-   (S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine;-   (S)-4′-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5′-bipyrimidin]-2′-amine;-   5-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine;-   (S)-4′-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;-   4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;-   4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;-   5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   (4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;-   (4S,5R)-3-[6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-pyrimidin-4-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-methyl-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;-   4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;-   4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-(cyclopropylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-(2,2-difluoroethoxy)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-[(4aS,7aR)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(4,4-difluoro-1-piperidyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl(pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;-   4-(difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[4-(2-methoxyethyl)piperazin-1-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(1,1-dioxo-1,4-thiazinan-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   3-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]oxazolidin-2-one;-   5-(4-((1R,2R,4S,5S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-6-(2R,4S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis(6,7-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-(6-amino-3-pyridyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-pyridyl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-pyrazin-2-yl-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1,2,4-triazol-1-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-1,2,4-triazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2H-tetrazol-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine.-   In another preferred embodiment, said compound of formula (I) is    selected from-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   4-(difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine;-   4′-(difluoromethyl)-2,6-dimorpholino-[4,5′-bipyrimidin]-2′-amine;-   4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine;-   4′-(difluoromethyl)-4,6-dimorpholino-[2,5′-bipyrimidin]-2′-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′-(difluoromethyl)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;-   5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   4′-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5′-bipyrimidin]-2′-amine;-   (S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine;-   (S)-4′-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5′-bipyrimidin]-2′-amine;-   5-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl(pyridin-2-amine;-   5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine;-   (S)-4′-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;-   4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine.-   In another preferred embodiment, said compound of formula (I) is    selected from-   4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;-   4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;-   5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   (4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;-   (4S,5R)-3-[6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-pyrimidin-4-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-methyl-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;-   4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;-   4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-(cyclopropylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-(2,2-difluoroethoxy)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-[(4aS,7aR)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(4,4-difluoro-1-piperidyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;-   4-(difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl(pyridin-2-amine;-   5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[4-(2-methoxyethyl)piperazin-1-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(1,1-dioxo-1,4-thiazinan-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   3-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]oxazolidin-2-one;-   5-(4-((1R,2R,4S,5S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-6-((2R,4S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl(pyridin-2-amine;-   5-[4,6-bis(6,7-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4-(6-amino-3-pyridyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-pyridyl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-pyrazin-2-yl-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1,2,4-triazol-1-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-1,2,4-triazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2H-tetrazol-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine.-   In another preferred embodiment, said compound of formula (I) is    selected from the group consisting of-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;    and-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred embodiment, said compound of formula (I) isselected from

-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another very preferred embodiment, said compound of formula (I) is4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine.

In another very preferred embodiment, said compound of formula (I) is4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another very preferred embodiment, said compound of formula (I) is5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine.

In another very preferred embodiment, said compound of formula (I) is5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl(pyridin-2-amine;and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another very preferred embodiment, said compound of formula (I) is(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine.

In another very preferred embodiment, said compound of formula (I) is(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred embodiment, said compound of formula (I) isselected from

-   4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;-   4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;-   5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine;-   5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;-   (4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;    and tautomers, solvates and pharmaceutically acceptable salts    thereof.

In another preferred embodiment, said compound of formula (I) is(4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one.

In another preferred embodiment, said compound of formula (I) is(4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred embodiment, said R¹ and R² are independently ofeach other a morpholinyl of formula (II). In one preferred embodiment,said R¹ is equal to R². In another preferred embodiment, said R¹ is notequal to R².

In another preferred embodiment, said R¹ and R² are independently ofeach other a morpholinyl of formula (II) and said 5- to 6-memberedheteroaryl ring W.

In another preferred embodiment, said R¹ and R² are independently ofeach other a morpholinyl of formula (II) and said saturated 4- to6-membered heterocyclic ring Z.

In another preferred embodiment, said R¹ and R² are independently ofeach other a morpholinyl of formula (II) and said OR¹².

In another preferred embodiment, said R¹ and R² are independently ofeach other a morpholinyl of formula (II) and said NR¹⁵R¹⁶.

In another preferred embodiment, within said morpholinyl of formula (II)

R³ and R⁴ are independently of each other H, C₁-C₃alkyl optionallysubstituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴ formtogether a bivalent residue —R⁵R⁶— selected from C₁-C₃alkyleneoptionally substituted with 1 to 4 F, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or anyof the structures

wherein the arrows denote the bonds in formula (II).

In the instance that R3 and R4 together form a bivalent residue and arebound to vicinal carbon atoms annulated morpholinyl substituents areformed. In the instance that R3 and R4 together form a bivalent residueand are spanning across the morpholine ring bridged morpholinylsubstituents are formed. In the instance that R3 and R4 together form abivalent residue and are bound to the same carbon atom of themorpholine, spiro morpholinyl substituents are formed.

In a preferred embodiment, R³ and R⁴ form together a bivalent residue—R⁵R⁶— selected from C₁-C₃alkylene optionally substituted with 1 to 4 F,—CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

and forming a bridged morpholinyl substituent.

In another preferred embodiment, said R¹ and R² are independently ofeach other a morpholinyl of formula (II), wherein R³ and R⁴ formtogether a bivalent residue leading to a bridged morpholinyl, wherein R³and R⁴ form together a bivalent residue —R⁵R⁶— selected fromC₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,—CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment, said morpholinyl of formula (II)

is independently of each other a morpholinyl of said formula (II),wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴ form together a bivalent residue—R⁵R⁶— selected from C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—,—CHFCHF—, —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of thestructures

wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment, said morpholinyl of formula (II) isindependently of each other a morpholinyl of said formula (II), whereinR³ and R⁴ are independently of each other H or CH₃.

In a further preferred embodiment, said morpholinyl of formula (II) isindependently of each other a morpholinyl of said formula (II), whereinR³ and R⁴ are independently of each other C₂-C₃alkyl, CH₂OH, CH₂CH₂OH,CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, orC(O)O—C₁-C₂alkyl; or R³ and R⁴ form together a bivalent residue —R⁵R⁶—selected from —CH₂— or C₃alkylene, preferably —CH₂—, —CH₂CF₂—, —CHFCHF—,—CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment, said morpholinyl of formula (II) isindependently of each other selected from

In a further preferred embodiment, said morpholinyl of formula (II) isindependently of each other selected from

In a further preferred embodiment, R¹ or R² is said 5- to 6-memberedheteroaryl ring W.

In a further preferred embodiment, said one to four heteroatoms of said5- to 6-membered heteroaryl ring W are solely N, and wherein said6-membered heteroaryl ring W is optionally substituted by 1 to 3 R⁸,wherein R⁸ is independently at each occurrence halogen, —OH, C₁-C₃alkyloptionally substituted with one or two OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ orN(CH₃)₂; and tautomers, solvates and pharmaceutically acceptable saltsthereof. Preferably, said 5- to 6-membered heteroaryl ring W containingone to four N is optionally substituted by 1 to 3 R⁸, wherein R⁸ isindependently at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂; and tautomers, solvates andpharmaceutically acceptable salts thereof.

In a further preferred embodiment, said heteroaryl ring W is a6-membered heteroaryl ring containing one to four heteroatoms, whereinsaid heteroatoms are solely N, and wherein said 6-membered heteroarylring W is optionally substituted by 1 to 3 R⁸, wherein R⁸ isindependently at each occurrence halogen, preferably fluorine, —OH,C₁-C₃alkyl, CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂; andtautomers, solvates and pharmaceutically acceptable salts thereof.

In a further preferred embodiment, said 5- to 6-membered heteroaryl ringW is selected from

In a further very preferred embodiment, said heteroaryl ring W is a6-membered heteroaryl ring selected from

In a further preferred embodiment, R¹ or R² is said 4- to 6-memberedheterocyclic ring Z.

In a further preferred embodiment, said heterocyclic ring Z is asaturated 5- to 6-membered heterocyclic ring Z containing 1 to 2heteroatoms independently selected from N, O and S, optionallysubstituted by 1 to 3 R⁹; wherein R⁹ is independently at each occurrencehalogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ orN(CH₃)₂; or two R⁹ substituents form together a bivalent residue—R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with 1 to 4F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

In a further preferred embodiment, said heterocyclic ring Z is asaturated 5- to 6-membered heterocyclic ring Z selected from

In an again further preferred embodiment, said heterocyclic ring Z is asaturated 5- to 6-membered heterocyclic ring Z selected from

In a preferred embodiment, said heterocyclic ring Z is an oxazolidinyloptionally substituted with halogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH,CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, ═O, —NH₂,NHCH₃ or N(CH₃)₂.

In a further preferred embodiment, said heterocyclic ring Z is

In a further preferred embodiment, R¹ or R² is said OR¹².

In a further preferred embodiment, said R¹² is C₁-C₃alkyl, CH₂F, CHF₂,CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, C₁-C₃alkoxy, C₃-C₆cycloalkyl,C₁-C₂alkyleneC₃-C₆cycloalkyl; Cycle-P or C₁-C₂alkyleneCycle-P, whereinCycle-P represents a saturated 4- to 6-membered heterocyclic ringcontaining 1 to 2 heteroatoms independently selected from N, O and S,optionally substituted by 1 to 2 R¹³, wherein R¹³ is independently ateach occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH,C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, —NH₂, NHCH₃ orN(CH₃); Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5-to 6-membered heteroaryl ring containing 1 to 2 heteroatomsindependently selected from N, O and S, optionally substituted by 1 to 3R¹⁴, wherein R¹⁴ is independently at each occurrence halogen, —OH,C₁-C₃alkyl, CH₂OH, CH₂CH₂OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,C₁-C₂alkoxyC₁-C₃alkyl, —NH₂, NHCH₃ or N(CH₃).

In a further preferred embodiment, said R¹² is C₁-C₃alkyl, CH₂F, CHF₂,CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, C₁-C₃alkoxy, C₃-C₆cycloalkyl,C₁-C₂alkyleneC₃-C₆cycloalkyl; Cycle-P or C₁-C₂alkyleneCycle-P, whereinCycle-P represents a saturated 4- to 6-membered heterocyclic ringcontaining 1 to 2 heteroatoms independently selected from O and S,preferably from O, optionally substituted by 1 to 2 R¹³, wherein R¹³ isindependently at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, —NH₂,NHCH₃ or N(CH₃); Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Qrepresents 5- to 6-membered heteroaryl ring containing 1 to 2heteroatoms, wherein said heteroatoms are N, and wherein said heteroarylring is optionally substituted by 1 to 3 R¹⁴, wherein R¹⁴ isindependently at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, —NH₂,NHCH₃ or N(CH₃).

In an again further preferred embodiment, said OR¹² is selected from

In a further preferred embodiment, R¹ or R² is said NR¹⁵R¹⁶.

In a further preferred embodiment, said R¹⁵ and R¹⁶ are independently ofeach other H, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl; Cycle-P or C₁-C₂alkyleneCycle-P,wherein Cycle-P represents a saturated 4- to 6-membered heterocyclicring containing 1 to 2 heteroatoms independently selected from O and S,preferably from O, optionally substituted by 1 to 2 R¹³, wherein R¹³ isindependently at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, —NH₂,NHCH₃ or N(CH₃); Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Qrepresents 5- to 6-membered heteroaryl ring containing 1 to 2heteroatoms, wherein said heteroatoms are N, and wherein said heteroarylring is optionally substituted by 1 to 3 R¹⁴, wherein R¹⁴ isindependently at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, —NH₂,NHCH₃ or N(CH₃).

In a further preferred embodiment, said R¹⁵ and R¹⁶ are independently ofeach other H, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl; Cycle-P or C₁-C₂alkyleneCycle-P,wherein Cycle-P represents a saturated 4- to 6-membered heterocyclicring containing 1 to 2 heteroatoms independently selected from O and S,preferably from O, optionally substituted by 1 to 2 R¹³, wherein R¹³ isindependently at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, —NH₂,NHCH₃ or N(CH₃); Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Qrepresents 5- to 6-membered heteroaryl ring containing 1 to 2heteroatoms, wherein said heteroatoms are N, and wherein said heteroarylring is optionally substituted by 1 to 3 R¹⁴, wherein R¹⁴ isindependently at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH,CH₂CH₂OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, —NH₂,NHCH₃ or N(CH₃).

In an again further preferred embodiment, said NR¹⁵R¹⁶ is selected from

In another preferred embodiment of the present invention, said R¹ andsaid R² are independently of each other a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II).

In another preferred embodiment of the present invention, said R¹ andsaid R² are independently of each other a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In a further preferred embodiment, said R¹ is equal to said R², and saidR¹ and said R² are independently of each other a morpholinyl of formula(II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment, said R¹ is equal to said R², and saidR¹ and said R² are independently of each other a morpholinyl of formula(II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In a further preferred embodiment of the present invention, said R¹ andsaid R² are independently of each other a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment of the present invention, said R¹ andsaid R² are independently of each other a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In a further preferred embodiment of the present invention, R¹ is equalto R², and said R¹ and said R² are a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment of the present invention, R¹ is equalto R², and said R¹ and said R² are a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II);

with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In another aspect and preferred embodiment, the present inventionprovides for a compound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; andwherein

R¹ and R² are independently of each other a morpholinyl of formula (II)

wherein the arrow denotes the bond in formula (I); and R¹ is not equalto R², and at least one of said R¹ and said R² are a morpholinyl offormula (II),

wherein R³ and R⁴ are independently of each other C₂-C₃alkyl, CH₂OH,CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴ form together a bivalent residue—R⁵R⁶— selected from —CH₂— or C₃alkylene, preferably —CH₂—, —CH₂CF₂—,—CHFCHF—, —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of thestructures

wherein the arrows denote the bonds in formula (II).

-   -   Preferably, said R³ and R⁴ form together a bivalent residue        —R⁵R⁶— selected from —CH₂— or C₃alkylene, preferably —CH₂—,        —CH₂CF₂—, —CHFCHF—, —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or        any of the structures

In a further aspect and preferred embodiment, the present inventionprovides for a compound of formula (I), wherein R¹ and R² areindependently of each other said morpholinyl of formula (II) and said 5-to 6-membered heteroaryl ring W, and tautomers, solvates andpharmaceutically acceptable salts thereof.

In a further aspect and preferred embodiment, the present inventionprovides for a compound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a 5- to 6-membered heteroaryl ring W containing one to four        heteroatoms independently selected from N, O and S, optionally        substituted by 1 to 3 R⁸, wherein R⁸ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl optionally substituted with        one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

and prodrugs, metabolites, tautomers, solvates and pharmaceuticallyacceptable salts thereof, preferably and tautomers, solvates andpharmaceutically acceptable salts thereof.

In a preferred embodiment, the present invention provides for a compoundof (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a 5- to 6-membered heteroaryl ring W containing one to four        heteroatoms, wherein said heteroatoms are solely N, and wherein        said 6-membered heteroaryl ring W is optionally substituted by 1        to 3 R⁸, wherein R⁸ is independently at each occurrence halogen,        —OH, C₁-C₃alkyl optionally substituted with one or two OH,        C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂; and tautomers, solvates        and pharmaceutically acceptable salts thereof. Preferably, said        5- to 6-membered heteroaryl ring W containing one to four N is        optionally substituted by 1 to 3 R⁸, wherein R⁸ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH,        CH₂F, CHF₂, CF₃, CH₂CF₃, C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a 5- to 6-membered heteroaryl ring W containing one to four        heteroatoms, wherein said heteroatoms are solely N, and wherein        said 5- to 6-membered heteroaryl ring W is optionally        substituted by 1 to 3 R⁸, wherein R⁸ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH, CH₂F,        CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a 5- to 6-membered heteroaryl ring W containing one to four        heteroatoms, wherein said heteroatoms are solely N, and wherein        said 5- to 6-membered heteroaryl ring W is optionally        substituted by 1 to 3 R⁸, wherein R⁸ is independently at each        occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH, CH₂F,        CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; andwherein R¹ and R² are independently of each other said morpholinyl offormula (II) and said 5- to 6-membered heteroaryl ring W, wherein saidR¹ and said R² are independently of each other selected from

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; andwherein R¹ and R² are independently of each other said morpholinyl offormula (II) and said 5- to 6-membered heteroaryl ring W, wherein saidR¹ and said R² are independently of each other selected from

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a further aspect and preferred embodiment, the present inventionprovides for a compound of formula (I), wherein R¹ and R² areindependently of each other said morpholinyl of formula (II) and saidsaturated 4- to 6-membered heterocyclic ring Z, and tautomers, solvatesand pharmaceutically acceptable salts thereof.

In a further aspect and preferred embodiment, the present inventionprovides for a compound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a saturated 4- to 6-membered heterocyclic ring Z containing        1 to 3 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

and prodrugs, metabolites, tautomers, solvates and pharmaceuticallyacceptable salts thereof, preferably and tautomers, solvates andpharmaceutically acceptable salts thereof.

In a further aspect and preferred embodiment, the present inventionprovides for a compound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a saturated 4- to 6-membered heterocyclic ring Z containing        1 to 3 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl optionally        substituted with one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

and prodrugs, metabolites, tautomers, solvates and pharmaceuticallyacceptable salts thereof, preferably and tautomers, solvates andpharmaceutically acceptable salts thereof; with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In a preferred embodiment, the present invention provides for a compoundof (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a saturated 5- to 6-membered heterocyclic ring Z containing        1 to 2 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH,        CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or N(CH₃)₂; or two R⁹        substituents form together a bivalent residue —R¹⁰R¹¹— selected        from C₁-C₃alkylene optionally substituted with 1 to 4 F,        —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the present invention provides for a compoundof (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl        optionally substituted with one or two OH, C₁-C₂fluoroalkyl,        C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or        R³ and R⁴ form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene optionally substituted with 1 to 4 F, —CH₂—O—CH₂—,        —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a saturated 5- to 6-membered heterocyclic ring Z containing        1 to 2 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein

    -   R⁹ is independently at each occurrence halogen, —OH, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

and tautomers, solvates and pharmaceutically acceptable salts thereof;

with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a saturated 5- to 6-membered heterocyclic ring Z containing        1 to 2 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein

    -   R⁹ is independently at each occurrence halogen, —OH, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or        N(CH₃)₂; or two R⁹ substituents form together a bivalent residue        —R¹⁰R¹¹— selected from C₁-C₃alkylene optionally substituted with        1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; and

R¹ and R² are independently of each other

-   -   (i) a morpholinyl of formula (II)

-   -   wherein the arrow denotes the bond in formula (I); and    -   wherein R³ and R⁴ are independently of each other H, C₁-C₃alkyl,        CH₂OH, CH₂CH₂OH, CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy,        C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴        form together a bivalent residue —R⁵R⁶— selected from        C₁-C₃alkylene, preferably C₁-C₂alkylene, —CH₂CF₂—, —CHFCHF—,        —CH₂CF₂CH₂—, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of the structures

-   -   -   wherein the arrows denote the bonds in formula (II); and

    -   (ii) a saturated 5- to 6-membered heterocyclic ring Z containing        1 to 2 heteroatoms independently selected from N, O and S,        optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently        at each occurrence halogen, —OH, C₁-C₃alkyl, CH₂OH, CH₂CH₂OH,        CH₂F, CHF₂, CF₃, CH₂CF₃, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,        C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or N(CH₃)₂; or two R⁹        substituents form together a bivalent residue —R¹⁰R¹¹— selected        from C₁-C₃alkylene optionally substituted with 1 to 4 F,        —CH₂—O—CH₂— or —O—CH₂CH₂—O—;

and tautomers, solvates and pharmaceutically acceptable salts thereof;

with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; andwherein R¹ and R² are independently of each other said morpholinyl offormula (II) and said saturated 4- to 6-membered heterocyclic ring Z,wherein said R¹ and said R² are independently of each other selectedfrom

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; andwherein R¹ and R² are independently of each other said morpholinyl offormula (II) and said saturated 4- to 6-membered heterocyclic ring Z,wherein said R¹ and said R² are independently of each other selectedfrom

with the provisos that

-   -   (a) when R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl; then R² is not 4-morpholinyl,        2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl;    -   (b) when R² is 4-morpholinyl, 2-methyl-4-morpholinyl,        3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,        8-aza-3-oxabicyclo[3.2.1]oct-8-yl,        3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,        4-methylpiperazin-1-yl, or 4-thiomorpholinyl; then R¹ is not        4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,        octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or        3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

In a further preferred embodiment, the present invention provides for acompound of (I)

wherein

X¹, X² and X³ are, independently of each other, N or CH; with theproviso that at least two of X¹, X² and X³ are N; Y is N or CH; andwherein R¹ and R² are independently of each other said morpholinyl offormula (II) and said saturated 4- to 6-membered heterocyclic ring Z,wherein said R¹ and said R² are independently of each other selectedfrom

In a further aspect and preferred embodiment, the present inventionprovides for a compound of formula (I), wherein R¹ and R² areindependently of each other said morpholinyl of formula (II) and saidOR¹².

In a further aspect and preferred embodiment, the present inventionprovides for a compound of formula (I), wherein R¹ and R² areindependently of each other said morpholinyl of formula (II) and saidNR¹⁵R¹⁶.

In another preferred embodiment, R¹ is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R² is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl.

In another preferred embodiment, R¹ is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R² is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and X¹, X² and X³ are N;and tautomers, solvates and pharmaceutically acceptable salts thereof.Preferably Y is N or CH; R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl;and R² is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and tautomers, solvatesand pharmaceutically acceptable salts thereof.

In a further preferred embodiment, R¹ is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R² is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and X¹ and X³ are N, andX² is CH; and tautomers, solvates and pharmaceutically acceptable saltsthereof. Preferably Y is N or CH; R¹ is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R² is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-y,4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and tautomers, solvatesand pharmaceutically acceptable salts thereof.

In a preferred embodiment, R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl;and R² is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and X¹ and X² are N, andX³ is CH; and tautomers, solvates and pharmaceutically acceptable saltsthereof. Preferably, Y is N or CH; R¹ is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R² is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and tautomers, solvatesand pharmaceutically acceptable salts thereof.

In a preferred embodiment, R¹ is 4-morpholinyl, 2-methyl-4-morpholinyl,3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl,8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl;and R² is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and X² and X³ are N, andX¹ is CH; and tautomers, solvates and pharmaceutically acceptable saltsthereof. Preferably, Y is N or CH; R¹ is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R² is 4-morpholinyl,2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl,3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl,4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and tautomers, solvatesand pharmaceutically acceptable salts thereof.

In a preferred embodiment, the compound of formula (I) is selected fromthe group consisting of

-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl(pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;    and-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the compound of formula (I) is selected fromthe group consisting of

-   4-(difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine;-   4′-(difluoromethyl)-2,6-dimorpholino-[4,5′-bipyrimidin]-2′-amine;-   5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′-(difluoromethyl)-2-morpholino-[4,5′-bipyrimidin]-2′-amine;-   5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;-   4′-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5′-bipyrimidin]-2′-amine;-   (S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine;-   (S)-4′-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5′-bipyrimidin]-2′-amine;-   5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl(pyridin-2-amine;-   2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′-(difluoromethyl)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;-   (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine;    and-   (S)-4′-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;    and tautomers, solvates and pharmaceutically acceptable salts    thereof.

In a preferred embodiment, the compound of formula (I) is selected fromthe group consisting of4-(difluoromethyl)-5-(6-morpholino-2-(piperazin-1-yl)pyrimidin-4-yl)pyridin-2-amineand4′-(difluoromethyl)-6-morpholino-2-(piperazin-1-yl)-[4,5′-bipyrimidin]-2′-amine;and tautomers, solvates and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the compound of formula (I) is selected fromthe group consisting of4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine and4′-(difluoromethyl)-4,6-dimorpholino-[2,5′-bipyrimidin]-2′-amine; andtautomers, solvates and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the compound of formula (I) is selected fromthe group consisting of

-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;-   5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;-   4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;-   4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;    and-   (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

and tautomers, solvates and pharmaceutically acceptable salts thereof.

Preferred are compounds wherein R¹ and R² are 4-morpholinyl.

Likewise preferred are compounds wherein R¹ and R² are3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

Likewise preferred are compounds wherein R¹ and R² are(S)-3-methyl-4-morpholinyl.

Likewise preferred are compounds wherein R¹ is 4-morpholinyl and R² is(S)-3-methyl-4-morpholinyl.

Likewise preferred are compounds wherein R¹ is 4-morpholinyl and R² is3-aza-8-oxabicyclo[3.2.1]oct-3-yl.

Likewise preferred are compounds wherein R¹ is 4-morpholinyl and R² is4-piperazin-1-yl.

Likewise preferred are compounds wherein R¹ is 4-morpholinyl and R² is4-thiomorpholinyl.

More preferred are compounds of formula (I) wherein R¹ and R² are4-morpholinyl, and Y is CH.

Equally preferred are compounds of formula (I) wherein R¹ and R² are4-morpholinyl, and Y is N.

More preferred are compounds of formula (I) wherein R¹ and R² are3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and Y is CH.

More preferred are compounds of formula (I) wherein R¹ and R² are(S)-3-methyl-4-morpholinyl, and Y is N.

More preferred are compounds of formula (I) wherein R¹ is 4-morpholinyland R² is 4-piperazin-1-yl, and Y is N.

More preferred are compounds of formula (I) wherein R¹ is 4-morpholinyland R² is (S)-3-methyl-4-morpholinyl, and Y is CH.

More preferred are compounds of formula (I) wherein R¹ is 4-morpholinyland R² is 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and Y is N.

More preferred are compounds of formula (I) wherein R¹ is(S)-3-methyl-4-morpholinyl and R² is 3-aza-8-oxabicyclo[3.2.1]oct-3-yl,and Y is CH.

More preferred are compounds of formula (I) wherein R¹ is(S)-3-methyl-4-morpholinyl and R² is 4-piperazin-1-yl, and Y is CH.

Likewise preferred are compounds of formula (I) wherein R¹ is(S)-3-methyl-4-morpholinyl and R² is 4-piperazin-1-yl, and Y is N.

More preferred are compounds of formula (I) wherein R¹ is 4-morpholinyland R² is 4-thiomorpholinyl, and Y is CH.

Likewise preferred are compounds of formula (I) wherein R¹ is4-morpholinyl and R² is 4-thiomorpholinyl, and Y is N.

Even more preferred are compounds of formula (I), wherein X¹, X² and X³are N.

Likewise preferred are compounds of formula (I), wherein X¹ and X³ areN, and X² is CH.

Most preferred are the following compounds shown by formula:

(The names of the corresponding structures were produced using ChemDrawUltra, version 13.0.1 as well as lower and upper software versionsthereof, CambridgeSoft Corp., Cambridge Mass.).

4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine

4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl(pyridin-2-amine

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine

5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine

4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine

4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine

4-(difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine

4′-(difluoromethyl)-2,6-dimorpholino-[4,5′-bipyrimidin]-2′-amine

4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine

4′-(difluoromethyl)-4,6-dimorpholino-[2,5′-bipyrimidin]-2′-amine

4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine

4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine

Further preferred are the following compounds

5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine

5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine

2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′-(difluoromethyl)-6-morpholino-[4,5′-bipyrimidin]-2′-amine

5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine

4′-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5′-bipyrimidin]-2′-amine

(S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine

(S)-4′-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5′-bipyrimidin]-2′-amine

5-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

(S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine

(S)-4′-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5′-bipyrimidin]-2′-amine

4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one

4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one

5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

(4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one

(4S,5R)-3-[6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-pyrimidin-4-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-methyl-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine

4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine

4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-(cyclopropylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4-(2,2-difluoroethoxy)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4-[(4aS,7aR)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-(4,4-difluoro-1-piperidyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol

Further preferred compounds are

4-(difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4,6-bis(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine

5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-[4-(2-methoxyethyl)piperazin-1-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-(1,1-dioxo-1,4-thiazinan-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

3-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]oxazolidin-2-one

5-(4-((1R,2R,4S,5S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-6-((2R,4S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

5-[4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4,6-bis(6,7-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

5-[4-(6-amino-3-pyridyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

4-(difluoromethyl)-5-[4-[4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-pyridyl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-pyrazin-2-yl-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1,2,4-triazol-1-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-1,2,4-triazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2H-tetrazol-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

Preparation of Compounds of the Invention

The compounds of the invention may be synthesized by synthetic routesthat include processes analogous to those well known in the chemicalarts, particularly in light of the description contained herein. Thestarting materials are generally available from commercial sources orare readily prepared using methods well known to those skilled in theart.

In preparing compounds of the invention, protection of remotefunctionality (e.g., primary or secondary amine) of intermediates may benecessary. The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. Suitable amino-protecting groups include tert-butyloxycarbonyl(BOC), bis-tert-butyloxycarbonyl or dimethylaminomethylenyl. The needfor such protection is readily determined by one skilled in the art. Fora general description of protecting groups and their use, see T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, NewYork, 1991.

Methods of Separation

In the methods of preparing the compounds of this invention, it may beadvantageous to separate reaction products from one another and/or fromstarting materials. The desired products of each step or series of stepsare separated and/or purified to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; high, medium and low pressure liquid chromatographymethods and apparatus; small scale analytical; and preparative thin orthick layer chromatography, as well as techniques of small scale thinlayer and flash chromatography.

Selection of appropriate methods of separation depends on the nature ofthe materials involved, for example, presence or absence of polarfunctional groups in chromatography, stability of materials in acidicand basic media in multiphase extraction, and the like. One skilled inthe art will apply techniques most likely to achieve the desiredseparation.

EXAMPLES

The Examples are intended to illustrate the present invention withoutrestricting it.

The chemical reactions described in the Examples may be readily adaptedto prepare a number of other lipid kinase inhibitors of the invention,and alternative methods for preparing the compounds of this inventionare deemed to be within the scope of this invention. For example, thesynthesis of non-exemplified compounds according to the invention may besuccessfully performed by modifications apparent to those skilled in theart, e.g., by appropriately protecting interfering groups, by utilizingother suitable reagents known in the art other than those described,and/or by making routine modifications of reaction conditions.Alternatively, other reactions disclosed herein or known in the art willbe recognized as having applicability for preparing other compounds ofthe invention.

As a rule, ^(1 H) NMR and mass spectra have been obtained for thecompounds prepared. In the Examples described below, unless otherwiseindicated, all temperatures are set forth in degrees Celsius (° C.).Reagents were purchased from commercial suppliers such as Sigma Aldrich,Fluorochem, Acros, Lancaster, TCI or Maybridge, and were used withoutfurther purification unless otherwise indicated. The reactions set forthbelow were done generally under a positive pressure of nitrogen or witha drying tube (unless otherwise stated) in anhydrous solvents, and thereaction flasks were typically fitted with rubber septa for theintroduction of substrates and reagents via syringe. Glassware was ovendried. Column chromatography was performed using Merck silica gel.^(1 H) NMR spectra were recorded on a Bruker instrument operating at 400MHz. ^(1 H) NMR spectra were obtained for solutions in variousdeuterated solvents such as CDCl₃, (CD₃)₂SO, CD₃OD or (CD₃)₂CO. Thechemical shift δ values were reported in ppm and corrected to the signalof the deuterated solvents (7.26 ppm for CDCl₃) or TMS (0 ppm). ¹⁹F NMRspectra were calibrated relative to CFCl₃ (δ=0 ppm) as externalstandard. ¹⁹F NMR spectra were recorded ^(1 H)-decoupled. When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), quint (quintet), br(broadened). Coupling constants, when given, are reported in Hertz (Hz).MALDI-ToF Mass spectra (MS) have been obtained on a Voyager-De™ Promeasured in m/z.

The following abbreviations are used hereinafter: BSA (bovine serumalbumin), DMSO (dimethyl sulfoxide), ESI (electronspray ionization), HCl(hydrochloric acid), M (molar), MALDI (Matrix-assisted LaserDesorption/Ionization), MS (mass spectrometry), PBS (phosphate bufferedsaline), TLC (thin layer chromatography).

Preparation of Intermediate Compounds

The following methods were used to prepare the intermediates compoundsused to produce compounds of formula (I).

Method 1:8-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(i1)

3-Oxa-8-azabicyclo[3.2.1]octane.HCl (Advanced ChemBlocks Inc, productnumber A-861, 2.00 g, 13.4 mmol, 2.0 eq.) and N,N-diisopropylethylamine(4.80 mL, 27.6 mmol, 4.1 eq.) are charged into a flask and dissolved indichloromethane (20 mL). The flask is placed in an ice bath and thesolution subsequently cooled down to 0° C. This solution is then addeddropwise to a solution of cyanuric chloride in dichloromethane (20 mL)at 0° C. The resulting reaction mixture is stirred overnight, while itis allowed to warm up to room temperature. Additional dichloromethane(100 mL) is added and the organic layer is washed with a saturatedaqueous solution of sodium bisulfate. The organic layer is then driedover anhydrous sodium sulfate, filtered and the solvent is evaporatedunder reduced pressure. Purification by flash chromatography(cyclohexane/ethyl acetate 4:1) gives the desired intermediate i1 as acolorless solid (79% yield). ¹H NMR (400 MHz, CDCl₃): δ4.70-4.54 (m,4H), 3.80-3.58 (m, 8H), 2.14-1.89 (m, 8H); MS (MALDI): m/z=338.4([M+H]⁺).

Method 1 is also used for the preparation of the following intermediatecompounds i2 to i10, and intermediates i79 to i81.

Reagent Structure NMR MS i2

¹H NMR (400 MHz, CDCl₃): δ 3.78 (m, 8 H), 3.70 (m, 8 H). MS (MALDI): m/z= 287.6 ([M + H]⁺). i3

¹H NMR (400 MHz), CDCl₃): δ 4.75-4.56 (m, 2 H), 4.34-4.30 (m, 2 H), 3.94(dd, ²J_(H,H) = 12.0 Hz, ³J_(H,H) = 4.0 Hz, 2 H), 3.74 (d, ²J_(H,H) =12.0 Hz, 2 H), 3.63 (dd, ²J_(H,H) = 12.0 Hz, ³J_(H,H) = 4.0 Hz, 2 H),3.49 (dt, ²J_(H,H) = 12..0 Hz, ³J_(H,H) = 4.0 Hz, 2 H), 3.25 (dt,²J_(H,H) = 12.0 Hz, ³J_(H,H) = 4.0 Hz, 2 H), 1.31 (d, ³J_(H,H) = 8.0 Hz,6 H). MS (MALDI): m/z = 314.4 ([M + H]⁺) i4

¹H NMR (400 MHz, CDCl₃: δ 3.81-3.72 (m, 8 H), 3.43 (s, 4 H), 1.43 (br s,12 H). MS (MALDI): m/z = 342.5 ([M + H]⁺). i5

¹H NMR (400 MHz, CDCl₃): δ 4.75-4.56 (m, 2 H), 4.34- 4.30 (m, 2 H), 3.94(dd, ²J_(H,H) = 12.0 Hz, ³J_(H,H) = 4.0 Hz, 2 H), 3.74 (d, ²J_(H,H) =12.0 Hz, 2 H), 3.63 (dd, ²J_(H,H) = 12.0 Hz, ³J_(H,H) = 4.0 Hz, 2 H),3.49 (dt, ²J_(H,H) = 12.0 Hz, ³J_(H,H) = 4.0 Hz, 2 H), 3.25 (dt,²J_(H,H) = 12.0 Hz, ³J_(H,H) = 4.0 Hz, 2 H), 1.31 (d, ³J_(H,H) = 8.0 Hz,6 H). MS (MALDI): m/z = 314.3 ([M + H]⁺). i6

¹H NMR (400 MHz, CDCl₃): δ 4.40-4.37 (m, 4 H), 3.74 (d, ³J_(H,H) = 11.6Hz, 4 H), 3.53 (dd, ³J_(H,H) = 11.6 Hz, ²J_(H,H) = 4.0 Hz, 4 H), 1.26(d, ³J_(H,H) = 6.9 Hz, 12 H). MS (MALDI): m/z = 342.8 ([M + H]⁺). i7

¹H NMR (400 MHz, CDCl₃): δ 4.53 (br s, 2 H), 4.36 (br s, 2 H), 4.12-4.06(m, 8 H), 3.92-3.83 (m, 8 H). MS (MALDI): m/z = 370.3 ([M]⁺). i8

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.36-4.21 (m, 4 H), 3.85-3.75 (m, 4 H),3.48-3.45 (m, 2 H), 3.40-3.34 (m, 2 H), 3.14-3.09 (m, 2 H), 1.72 (m, 4H), 0.82 (m, 6 H). MS (MALDI): m/z = 342.3 ([M]⁺). i9

¹H NMR (400 MHz, (CD₃)₂SO): δ 3.64(m, 8 H), 3.351-3.48 (m, 4 H), 2.46-2.38 (m, 4 H), 2.20-2.16 (m, 4 H), 1.73-1.66 (m, 4 H). MS (MALDI): m/z =366.7 ([M]⁺). i10

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.40-4.25 (m, 2 H), 4.20-4.05 (m, 2 H),4.08 (m, 2 H), 3.95 (m, 2 H), 3.83 (m, 4 H), 3.08 (m, 2 H), 2.30 (m, 2H), 0.98 (m, 6 H), 0.48 (m, 6 H). MS (MALDI): m/z = 370.4 ([M]⁺). i79

¹H NMR (400 MHz, CDCl₃): δ 4.59-4.31 (m, 4 H), 3.66- 3.46 (m, 4 H), 2.70(m, 4 H), 1.14 (m, 12 H). MS (MALDI): m/z = 342.4 ([M + H]⁺). i80

¹H NMR (400 MHz, CDCl₃): δ 3.73-3.64 (m, 8 H), 3.57 (s, 2 H), 3.51 (s, 2H), 1.14 (s, 12 H). MS (MALDI): m/z = 342.3 ([M + H]⁺). i81

¹H NMR (400 MHz, CDCl₃): δ 4.41 (br s, 4 H), 4.32- 4.16 (m, 4 H),3.24-3.10 (m, 4 H), 1.99-1.84 (m, 4 H), 1.84-1.67 (m, 4 H). MS (MALDI):m/z = 338.4 ([M + H]⁺)

Method 2: 2,4-dichloro-6-morpholino-1,3,5-triazine (i11)

To a solution of cyanuric chloride (18.1 g, 0.100 mol, 1.0 eq.) indichloromethane (200 mL) is dropwise added a cold solution of morpholine(17.4 g, 0.200 mol, 2.0 eq.) at −78° C. over 2 hours. The resultingmixture is allowed to warm to 0° C. with stirring and mixed with an icecold saturated solution of sodium bisulfate in water. The phases areseparated and the organic phase is washed with half concentrated brinedried over sodium sulfate and evaporated to yield the title compound i11as a colorless solid. ¹H NMR (400 MHz, CDCl₃): δ3.90-3.86 (m, 4H),3.77-3.72 (m, 4H).

Method 3:8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(i12)

3-Oxa-8-azabicyclo[3.2.1]octane.HCl (Advanced ChemBlocks Inc, productnumber A-861, 200 mg, 1.34 mmol, 1.1 eq.) and N,N-diisopropylethylamine(470 μL, 2.69 mmol, 2.1 eq.) are charged in a flask and dissolved inethanol (3 mL). The flask is placed in an ice bath. A solution ofcompound i11 (300 mg, 1.28 mmol, 1.0 eq.) in ethanol (2 mL) is added tothe above solution at 0° C. The resulting mixture is stirred overnight,while allowing it to warm up to room temperature. Deionized water (20mL) is added and the aqueous layer is extracted with ethyl acetate (3×30mL). The combined organic layer is dried over anhydrous sodium sulfate,filtered and the solvent is evaporated under reduced pressure.Purification by flash chromatography (cyclohexane/ethyl acetate 9:1→8:2)gives the desired intermediate i12 as a colorless solid (78% yield). ¹HNMR (400 MHz, CDCl₃): δ4.69-4.56 (m, 2H), 3.86-3.59 (m, 12H), 2.12-1.91(m, 4H); MS (MALDI): m/z=312.7 ([M+H]⁺).

Method 3 is also used for the preparation of the following intermediatecompounds i13 to i16.

Reagent Structure NMR i13

¹H NMR (400 MHz, CDCl₃): δ 4.71-4.61 (m, 1 H), 4.34-4.31 (m, 1 H),3.96-3.92 (m, 1 H), 3.79-3.70 (m, 9 H), 3.65-3.61 (m, 1 H), 3.51- 3.45(m, 1 H), 3.29-3.21 (m, 1 H), 1.36- 1.30 (d, ³J_(H,H) = 6.9 Hz, 3 H).i14

¹H NMR (400 MHz, CDCl₃): δ 3.79-3.71 (m, 12 H), 3.46 (m, 4 H), 1.48 (s,9 H). i15

¹H NMR (400 MHz, CDCl₃): δ 4.12-3.98 (m, 4 H), 3.84-3.70 (m, 4 H),3.70-3.62 (m, 4 H), 2.66-2.56 (m, 4 H). i16

¹H NMR (400 MHz, CDCl₃): δ 3.77 (m, 4 H), 3.68-3.63 (m, 8 H), 3.44 (s, 2H), 1.44 (s, 6 H).

Method 4: (S)-4-(4,6-dichloro-1,3,5-triazin-2-yl)-3-methylmorpholine(i17)

To a solution of cyanuric chloride (450 mg, 2.44 mol, 1.0 eq.) indichloromethane (4 mL) is slowly added a solution of(S)-3-methylmorpholine (Activate Scientific, product number AS3424, 0.28mL, 2.44 mol, 1.0 eq.) and triethylamine (0.35 mL, 2.51 mol, 1.02 eq.)in dichloromethane (2 mL) at −50° C. The resulting mixture is stirredfor 2 hours at −50° C., then allowed to warm to 0° C. with stirring andmixed with an ice cold saturated solution of sodium bisulfate in water.The phases are separated and the organic phase is washed with brinedried over sodium sulfate and evaporated to yield the title compound i17as a colorless solid (95% yield). ¹H NMR (400 MHz, CDCl₃): δ4.78-4.69(m, 1H), 4.43-4.39 (m, 1H), 3.98-3.96 (m, 1H), 3.78-3.76 (m, 1H),3.67-3.65 (m, 1H), 3.51-3.47 (m, 1H), 3.40-3.37 (m, 1H), 1.36 (m, 3H).

Method 5:8-(4-chloro-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(i18)

3-Oxa-8-azabicyclo[3.2.1]octane.HCl (Advanced ChemBlocks Inc, productnumber A-861, 383 mg, 2.55 mmol, 1.1 eq.) and N,N-diisopropylethylamine(1.0 mL, 5.60 mmol, 2.4 eq.) are charged in a flask and dissolved inethanol (4 mL). The flask is placed in an ice bath. A solution ofcompound i17 (580 mg, 2.33 mmol, 1.0 eq.) in ethanol (2 mL) is added tothe above solution at 0° C. The resulting mixture is stirred for 4hours, while allowing it to warm up to room temperature. Deionized water(20 mL) is added and the aqueous layer is extracted with ethyl acetate(3×30 mL). The combined organic layer is dried over anhydrous sodiumsulfate, filtered and the solvent is evaporated under reduced pressure.Purification by flash chromatography (cyclohexane/ethyl acetate 9:1→8:2)gives the desired intermediate i18 as a colorless solid (88% yield). ¹HNMR (400 MHz, CDCl₃): δ4.75-4.52 (m, 3H), 4.37-4.24 (m, 1H), 3.95-3.92(m, 1H), 3.73-3.70 (m, 3H), 3.64-3.61 (m, 3H), 3.52-3.42 (m, 1H),3.29-3.17 (m, 1H), 2.11-1.89 (m, 4H), 1.31 (m, 3H).

Method 6: tert-butyl4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (i19)

To a cooled (−50° C.) solution of cyanuric chloride (1.0 g, 5.42 mmol,1.0 eq.) in dichloromethane (4 mL) is added dropwise a solution oftert-butyl piperazine-1-carboxylate (Sigma, product number 343536, 1.02g, 5.48 mmol, 1.01 eq.) and triethylamine (0.767 mL, 5.53 mmol, 1.02eq.) in dichloromethane (2 mL). The resulting reaction mixture isstirred at −50° C. for 4 hours. A saturated aqueous solution of sodiumbisulfate (10 mL) and dichloromethane (20 mL) are added. The mixture istransferred to a separating funnel. The organic layer is separated,washed with a saturated aqueous solution of sodium bisulfate (20 mL),dried over anhydrous sodium sulfate, filtered and then the solvent isevaporated under reduced pressure to give pure intermediate i19 (80%yield). ¹H NMR (400 MHz, CDCl₃): δ3.88-3.85 (m, 4H), 3.53-3.51 (m, 4H),1.49 (m, 9H).

Method 7: tert-butyl4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate(i20)

3-Oxa-8-azabicyclo[3.2.1]octane.HCl (Advanced ChemBlocks Inc, productnumber A-861, 235 mg, 1.57 mmol, 1.0 eq.) and N,N-diisopropylethylamine(592 μL, 3.14 mmol, 2.1 eq.) are charged in a flask and dissolved inethanol (6 mL). The flask is placed in an ice bath. A solution ofcompound i19 (500 mg, 1.5 mmol, 1.0 eq.) in ethanol (2 mL) is added tothe above solution at 0° C. The resulting mixture is stirred overnight,while allowed to warm up to room temperature. Deionized water (10 mL) isadded and the aqueous layer is extracted with ethyl acetate (3×30 mL).The combined organic layer is dried over anhydrous sodium sulfate,filtered and the solvent is evaporated under reduced pressure.Purification by flash chromatography (cyclohexane/ethyl acetate 8:2)gave the desired intermediate i20 as a colorless solid (77% yield). ¹HNMR (400 MHz, CDCl₃): δ4.68-4.60 (m, 2H), 3.76-3.70 (m, 6H), 3.64-3.62(m, 2H), 3.47-3.45 (m, 4H), 2.08-1.95 (m, 4H), 1.48 (br s, 9H); MS(MALDI): m/z=411.8 ([M+H]⁺).

Method 7 is also used for the preparation of the following intermediatecompound i21.

Reagent Structure NMR MS i21

¹H NMR (400 MHz, CDCl₃): δ 4.76-4.61 (m, 1 H), 4.35-4.30 (m, 1 H), 3.94(dd, ²J_(H,H) = 12 Hz, ³J_(H,H) = 4.0 Hz, 1 H), 3.76-3.72 (m, 5 H), 3.65(dd, ²J_(H,H) = 12 Hz, ³J_(H,H) = 4.0 Hz, 1 H), 3.51-3.44 (m, 5 H), 3.25(dt, ²J_(H,H) = 12 Hz, ³J_(H,H) = 4.0 Hz, 1 H), 1.48 (s, 9 H), 1.30 (d,³J_(H,H) = 8.0 Hz, 3 H). MS (MALDI): m/z = 399.1 ([M + H]⁺).

Method 8: 4,4′-(6-chloropyrimidine-2,4-diyl)dimorpholine (i22) and4,4′-(2-chloropyrimidine-4,6-diyl)dimorpholine (i23)

2,4,6-Trichloropyrimidine (Manchester Organics, product number Y17832,11.2 g, 61 mmol, 1.0 eq.), N,N-diisopropylethylamine (23.3 mL, 134.2mmol, 2.2 eq.) and morpholine (11.7 mL, 134.2 mmol, 2.2 eq.) are chargedin a flask and dissolved in ethanol (120 mL). The flask is equipped witha refluxed condenser and placed in an oil bath preheated at 100° C. Thereaction mixture is stirred at this temperature for 18 hours. After thistime, the reaction mixture is cooled down to room temperature andvolatiles are removed under reduced pressure. The resulting mixture isdissolved in dichloromethane (100 mL) and washed twice with an aqueoussolution of sodium bisulfate (2×80 mL). The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure using a rotary evaporator. Products i22 and i23 are isolated byflash chromatography on silica gel (cyclohexane/ethyl acetate 3:1→1:1).The product fractions are pooled and evaporated to yield i22 as acolorless powder (13.8 g, 80%) and i23 as a colorless powder (2.2 g, 13%yield).

4,4′-(6-chloropyrimidine-2,4-diyl)dimorpholine (i22): ¹H NMR (400 MHz,CDCl₃): δ5.85 (s, 1H), 3.71-3.75 (m, 12H), 3.52-3.55 (m, 4H); MS(MALDI): m/z: 285.4 ([M+H]⁺).

4,4′-(2-chloropyrimidine-4,6-diyl)dimorpholine (i23): ¹H NMR (400 MHz,CDCl₃): δ5.38 (s, 1H), 3.73-3.76 (m, 8H), 3.52-3.54 (m, 8H); MS (MALDI):m/z: 285.2 ([M+H]⁺).

Method 9:8-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloropyrimidin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(i24)

A solution of 2,4,6-trichloropyrimidine (0.676 mL, 5.88 mmol, 1.0 eq.),3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.76 g, 11.8 mmol, 2.0eq.), and N,N-diisopropylethylamine (4.10 mL, 23.5 mmol, 4.0 eq.) inethyl acetate (18 volumes) is heated for 16 hours (100° C.). Then, thesolvent is removed under reduced pressure and the residue is dissolvedin dichloromethane (60 volumes) and washed with a saturated aqueoussodium bisulfate (3×60 volumes). The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. Purification by column chromatography on silica gel(cyclohexane/ethyl acetate 3:1→1:1) affords the desired intermediate i24as a colorless solid (1.23 g, 62%). ¹H NMR (400 MHz, CDCl₃): δ5.80 (s,1H), 4.59 (s, 2H), 4.35 (m, 2H), 3.76 (t, ²J_(H,H)=10.8 Hz, 4H), 3.59(d, ²J_(H,H)=10.8 Hz, 4H), 2.03 (m, 8H); MS (MALDI): m/z=337.7 ([M+H]⁺).

Method 9 is also used for the preparation of the following intermediatecompound i25.

Reagent Structure NMR MS i25

¹H NMR (400 MHz, CDCl₃): δ 5.83 (s, 1 H), 4.64-4.57 (m, 1 H), 4.27 (dd,³J_(H,H) = 2.4 Hz, ²J_(H,H) = 13.5 Hz, 1 H), 4.20-4.11 (m, 1 H),3.97-3.87 (m, 3 H), 3.77-3.63 (m, 4 H), 3.56-3.46 (m, 2 H), 3.26-3.15(m, 2 H), 1.28 (d, ³J_(H,H) = 3.2 Hz, 3 H), 1.27 (d, ³J_(H,H) = 3.2 Hz,3H). MS (MALDI): m/z = 313.6 ([M + H]⁺).

Method 10: 4-(4,6-dichloropyrimidin-2-yl)morpholine (i26) and4-(2,6-dichloropyrimidin-4-yl)morpholine (i27)

To a solution of 2,4,6-trichloropyrimidine (14.0 mL, 122 mmol, 1.0 eq.)in EtOH (150 mL) is added a solution of morpholine (11.2 mL, 256 mmol,2.1 eq.) and N,N-diisopropylethylamine (44.6 mL, 256 mmol, 2.1 eq.) inEtOH (150 mL) dropwise at 0° C. The reaction mixture is stirredovernight at room temperature and the solvent is removed under reducedpressure. The crude product is extracted with dichloromethane (3×100 mL)and the organic phase is successively washed with saturated aqueoussodium bisulfate (3×400 mL). The combined organic layers are dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. The crude mixture is purified by flash column chromatography(SiO₂, cyclohexane/ethyl acetate 9:1→3:1) to yield i26 (5.02 g, 18%) andi27 (16.7 g, 59%), both as colorless solids.

4-(4,6-dichloropyrimidin-2-yl)morpholine (i26): ¹H NMR (400 MHz, CDCl₃):δ6.56 (s, 1H), 3.78 (m, 4H) 3.74 (m, 4H).

4-(2,6-dichloropyrimidin-4-yl)morpholine (i27): ¹H NMR (400 MHz, CDCl₃):δ6.41 (s, 1H), 3.78 (m, 4H), 3.65 (m, 4H).

Method 11:(S)-4-(2-chloro-6-morpholinopyrimidin-4-yl)-3-methylmorpholine (i28)

A solution of i27 (694 mg, 2.97 mmol, 1.0 eq.), (S)-3-methylmorpholine(0.500 mL, 4.46 mmol, 1.5 eq.) and N,N-diisopropylethylamine (1.29 mL,7.43 mmol, 2.5 eq.) in EtOH (5.0 mL) is heated to reflux for 3 days.Then, the solvent is removed under reduced pressure. The residue isdissolved in dichloromethane (60 volumes) and washed with saturatedaqueous sodium bisulfate (3×60 volumes). The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude mixture is purified by flash chromatography (SiO₂,cyclohexane/ethyl acetate 3:1→1:1) to afford the title compound(S)-4-(2-chloro-6-morpholinopyrimidin-4-yl)-3-methylmorpholine (i28) asa colorless solid (425 mg, 48%). ¹H NMR (400 MHz, CDCl₃): δ5.85 (s, 1H),4.62 (dd, ²J_(H,H)=13.6 Hz, ³J_(H,H)=2.9 Hz, 1H), 4.25 (dd,²J_(H,H)=13.6 Hz, ³J_(H,H)=2.9 Hz, 1H), 3.93 (dd, ²J_(H,H)=11.4 Hz,³J_(H,H)=3.8 Hz, 1H), 3.75, (t, ³J_(H,H)=5.0 Hz, 4H), 3.71 (s, 1H), 3.66(dd, ²J_(H,H)=11.3 Hz, ³J_(H,H)=3.2 Hz, 1H), 3.53 (m, 5H), 3.23 (m, 1H),1.26 (d, ²J_(H,H)=11.3 Hz, 3H); MS (MALDI): m/z=299.4 ([M+H]⁺).

Method 11 is also used for the preparation of the following intermediatecompound i29.

Reagent Structure NMR MS i29

¹H NMR (400 MHz, CDCl₃): δ 5.86 (s, 1 H), 4.60 (br s, 2 H), 3.80-3.72(m, 6 H), 3.62-3.56 (m, 2 H), 3.56-3.50 (m, 4 H), 2.08- 1.90 (m, 4 H).MS (MALDI): m/z = 309.6 ([M + H]⁺).

Method 12:(S)-4-(6-chloro-2-morpholinopyrimidin-4-yl)-3-methylmorpholine (i30)

A solution of (S)-3-methylmorpholine (194 mg, 1.32 mmol, 1.5 eq.), i26(300 mg, 1.28 mmol, 1.0 eq.) and N,N-diisopropylethylamine (3.0 eq.) inDMF (17 volumes) is heated for 16 hours (130° C.). Then, the solvent isremoved under reduced pressure. The residue is dissolved indichloromethane (100 volumes) and washed with saturated aqueous sodiumbisulfate (3×100 volumes). The organic layer is dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude mixture is purified by flash chromatography (SiO₂,cyclohexane/ethyl acetate 5:1) to afford the title compound i30 as acolorless solid (257 mg, 67%). ¹H NMR (400 MHz, CDCl₃): δ5.84 (s, 1H),4.18 (m, 1H), 3.94 (m, 2H), 3.71 (m, 10H), 3.53, (dt, ²J_(H,H)=12.0 Hz,³J_(H,H)=3.1 Hz, 1H), 3.20 (dt, ²J_(H,H)=12.8 Hz, ³J_(H,H)=3.8 Hz, 1H),1.27 (d, ³J_(H,H)=6.8 Hz, 3H); MS (MALDI): m/z=298.4 ([M]+).

Method 13: 4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)morpholin-3-one(i31)

A round bottom flask was charged with compound i11 (5.37 g, 22.9 mmol,1.5 eq), morpholine-3-one (1.54 g, 15.3 mmol, 1.0 eq),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (530 mg, 0.915 mmol,0.06 eq.), cesium carbonate (9.95 g, 30.5 mmol, 2.0 eq) andpalladium(II) acetate (383 mg, 0.170 mmol, 0.04 eq.). The reactionmixture was flushed with nitrogen and 1,4-dioxane (100 mL) was added.The reaction mixture was stirred at reflux (100° C.) for 4 hours. Thereaction mixture was cooled to room temperature and filtered. The filtercake was washed with dichloromethane (2×30 mL). Solvents were removedunder reduced pressure and the crude product was purified using silicagel chromatography (cyclohexane/ethyl acetate 1:0→1:3) to yield thetitle compound i31 as a colorless solid (390 mg, 31%). ¹H NMR (400 MHz,CDCl₃): δ4.32 (s, 2H), 4.03-3.97 (m, 4H), 3.93-3.86 (m, 4H), 3.75-3.73(m, 4H); MS (MALDI): m/z=299.6 ([M+H]⁺).

Method 14:8-(4,6-dichloro-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(i32)

A solution of cyanuric chloride (1.97 g, 10.7 mmol, 1.0 eq.) indichloromethane (10 mL) is cooled to −50° C. A solution of3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.60 g, 10.7 mmol, 1.0eq.) and N,N-diisopropylethylamine (3.73 mL, 21.4 mmol, 2.0 eq.) indichloromethane (40 mL) is slowly added over a period of 5 hours. Themixture is stirred for another 5 hours at this temperature. Then,dichloromethane (20 mL) and saturated aqueous sodium bisulfate (50 mL)are added and the mixture is allowed to warm to room temperature. Thelayers are separated and the organic layer is washed with saturatedaqueous sodium bisulfate (2×50 mL). The organic layer is dried overanhydrous sodium sulfate and the solvent is removed under reducedpressure. The crude mixture is recrystallized fromn-heptane/dichloromethane (20 mL/13 mL) to afford the title compound8-(4,6-dichloro-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(i32) as a colorless solid (2.47 g, 47%). ¹H NMR (400 MHz, CDCl₃): δ4.74(m, 2H), 3.72 (d, ³J_(H,H)=1.5 Hz, 4H), 2.08 (m, 4H).

Method 14 is also used for the preparation of the following intermediatecompounds i33 and i34.

Reagent Structure NMR i33

¹H NMR (400 MHz, CDCl₃): δ 4.54-4.60 (m, 1 H), 4.20 (dd, ³J_(H,H) = 2.9Hz, ²J_(H,H) = 14 Hz, 1 H), 3.92 (dd, ³J_(H,H) = 3.4 Hz, ²J_(H,H) = 12Hz, 1 H), 3.71 (d, ²J_(H,H) = 12 Hz, 1 H), 3.57 (dd, ³J_(H,H) = 3.2 Hz,²J_(H,H) = 12 Hz, 1 H), 3.42 (m, 1 H), 3.32 (m, 1 H), 1.27 (d, ³J_(H,H)= 6.9 Hz, 3 H). i34

¹H NMR (400 MHz, (CD₃)₂SO): δ 3.88- 3.81 (m, 4 H), 3.51 (s, 2 H), 1.46(s, 6 H).

Method 15:9-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane(i35)

To a solution of 3,7-dioxa-9-azabicyclo[3.3.1]nonane (184 mg, 0.700mmol, 1.0 eq.) and N,N-diisopropylethylamine (0.170 mL, 0.970 mmol, 1.4eq.) in 1,4-dioxane (1.0 mL) a solution of i32 (100 mg, 0.770 mmol, 1.1eq.) in 1,4-dioxane (2.0 mL) is added. The resulting mixture is heatedfor 1 hour at 70° C. Then, dichloromethane (50 mL) and water (50 mL) areadded. The aqueous layer is extracted with dichloromethane (3×50 mL),the combined organic layers are dried over anhydrous sodium sulfate andthe solvent is evaporated. The crude mixture is purified by automatedflash chromatography on silica gel (cyclohexane/ethyl acetate 2:1→0:1)to afford the title compound9-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane(i35) as a colorless solid (192 mg, 77%). ¹H NMR (400 MHz, (CD₃)₂SO):δ4.70 (m, 1H), 4.55 (m, 2H), 4.44 (m, 1H), 4.12 (m, 4H), 3.90 (m, 4H),3.72 (m, 2H), 3.64 (m, 2H), 2.08 (m, 2H), 1.97 (m, 2H); MS (MALDI):m/z=354.3 ([M]⁺).

Method 16:9-(4-chloro-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane(i36)

To a solution of 3,7-dioxa-9-azabicyclo[3.3.1]nonane (173 mg, 1.27 mmol,1.05 eq.) and N,N-diisopropylethylamine (0.50 mL, 2.52 mmol, 2.1 eq.) intetrahydrofuran (5 mL) a solution of i33 (300 mg, 2.52 mmol, 2.1 eq.) in1,4-dioxane (2.0 mL) is added. The resulting mixture is heated for 2hours (70° C.). Then, ethyl acetate (20 mL) and saturated aqueous sodiumbisulfate (20 mL) are added. The phases are separated and the organiclayer is washed with saturated aqueous sodium bisulfate (2×20 mL). Theorganic layer is dried over anhydrous sodium sulfate and the solvent isremoved under reduced pressure. The crude mixture is purified byautomated flash chromatography (SiO₂, cyclohexane/ethyl acetate 2:1→0:1)to afford the title compound i36 as a colorless solid (316 mg, 76%). ¹HNMR (400 MHz, (CD₃)₂SO): δ4.55-4.53 (m, 1H), 4.42 (m, 1H), 4.32 (m, 1H),4.25-4.16 (m, 1H), 4.01-3.97 (m, 4H), 3.87 (dd, ³J_(H,H)=3.8 Hz,²J_(H,H)=11.2 Hz, 1H), 3.73-3.65 (m, 5H), 3.53 (dd, ³J_(H,H)=3.0 Hz,²J_(H,H)=11.6 Hz, 1H), 3.38 (m, 1H), 3.15 (m, 1H), 1.20 (d, ³J_(H,H)=6.9Hz, 3H).

Method 16 is also used for the preparation of the following intermediatecompounds i37 to i53, and intermediate i82.

Reagent Structure NMR MS i37

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.58-4.50 (m, 1 H), 4.44-4.35 (m, 2 H),4.25-4.12 (m, 1 H), 3.90- 3.86 (m, 1 H), 3.75- 3.65 (m, 3 H), 3.56- 3.49(m, 3 H), 3.38 (m, 1 H), 3.16 (m, 1 H), 1.25 (d, ³J_(H,H) = 6.9 Hz, 6H), 1.19 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI): m/z = 328.2 ([M +H]⁺). i38

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.54-4.46 (m, 1 H), 4.18-4.13 (m, 1 H),3.88 (m, 1 H), 3.80- 3.65 (m, 5 H), 3.54 (m, 1 H), 3.44-3.36 (m, 3 H),3.18 (m, 1 H), 1.44 (s, 6 H), 1.21 (d, ³J_(H,H) = 6.9 Hz, 3 H). i39

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.65-4.51 (m, 2 H), 4.31-4.20 (m, 2 H),3.66 (m, 3 H), 3.69- 3.56 (m, 2 H), 3.54- 3.48 (m, 3 H), 3.42- 3.35 (m,2 H), 3.31 (s, 3 H), 3.21-3.13 (m, 2 H), 1.21 (d, ³J_(H,H) = 6.9 Hz, 3H). MS (MALDI): m/z = 344.2 ([M + H]⁺). i40

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.55-4.51 (m, 1 H), 4.42-4.35 (m, 2 H),4.12-4.25 (m, 2 H), 4.04- 4.07 (m, 1 H), 3.86- 3.88 (m, 1 H), 3.78- 3.75(m, 2 H), 3.69-3.65 (m, 1 H), 3.55-3.51 (m, 1 H), 3.38 (m, 1 H), 3.20-3.13 (m, 1 H), 2.68 (m, 1 H), 1.81 (m, 1 H), 1.20 (d, ³J_(H,H) = 6.9 Hz,3 H). i41

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.69-4.53 (m, 3 H), 4.31-4.15 (m, 1 H),3.93-3.78 (m, 3 H), 3.71- 3.53 (m, 4 H), 3.42- 3.35 (m, 1 H), 3.22- 3.16(m, 1 H), 3.12-3.08 (m, 1 H), 1.81 (m, 1 H), 1.21 (d, ³J_(H,H) = 6.9 Hz,3 H). i42

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.95-4.88 (m, 1 H), 4.64 (m, 1 H), 4.54(m, 1 H), 4.31- 4.09 (m, 1 H), 3.89- 3.85 (m, 1 H), 3.75- 3.73 (m, 2 H),3.66-3.63 (m, 2 H), 3.52 (m, 1 H), 3.45-3.32 (m, 3 H), 3.18- 3.12 (m, 1H), 1.90- 1.83 (m, 2 H), 1.21 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI):m/z = 312.2 ([M + H]⁺). i43

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.94-4.88 (m, 1 H), 4.64 (m, 1 H), 4.54(m, 1 H), 4.29- 4.12 (m, 1 H), 3.89- 3.85 (m, 1 H), 3.75- 3.73 (m, 2 H),3.66-3.63 (m, 2H), 3.52 (m, 1 H), 3.45-3.32 (m, 2 H), 3.18- 3.12 (m, 1H), 1.90- 1.83 (m, 2 H), 1.21 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI):m/z = 312.2 ([M + H]⁺). i44

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.62-4.17 (m, 4 H), 3.88 (m, 1 H), 3.68(m, 1 H), 3.54- 3.51 (m, 1 H), 3.41 (m, 1 H), 3.25-3.15 (m, 4 H), 1.21(m, 3 H). MS (MALDI): m/z = 326.8 ([M + H]⁺). i45

¹H NMR (400 MHz, (CD₃)₂SO): δ 8.55-40 (m, 1 H), 4.65-4.77 (m, 1 H),4.36-4.01 (m, 3 H), 3.83 (m, 1 H), 3.62 (m, 1 H), 3.52 (m, 1 H), 3.35(m, 1 H), 3.10 (m, 1 H), 1.18 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI):m/z = 312.1 ([M + H]⁺). i46

¹H NMR (400 MHz, (CD₃)₂SO): δ 8.12-7.89 (m, 1 H), 4.52 (m, 1 H), 4.16(m, 1 H), 3.88 (m, 1 H), 3.68 (m, 1 H), 3.52 (m, 1 H), 3.35 (m, 2 H),3.10 (m, 2 H), 1.18 (d, ³J_(H,H) = 6.9 Hz, 3 H), 1.04 (m, 1 H), 0.42 (m,2 H), 0.20 (m, 2 H). MS (MALDI): m/z = 284.9 ([M + H]⁺). i47

¹H NMR (400 MHz, (CD₃)₂SO): δ 5.10-4.97 (m, 2 H), 4.70-4.54 (m, 1 H),4.25 (m, 1 H), 3.91 (m, 1 H), 3.71 (m, 1 H), 3.57 (m, 1 H), 3.41 (m, 1H), 3.29 (m, 1 H), 1.25 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI): m/z =313.6 ([M + H]⁺). i48

¹H NMR (400 MHz, (CD₃)₂SO): δ 6.37 (m, 1 H), 4.68-4.53 (m, 3 H), 4.25(m, 1 H), 3.90 (m, 1 H), 3.70 (m, 1 H), 3.55 (m, 1 H), 3.41 (m, 1 H),3.25 (m, 1 H), 1.24 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI): m/z = 295.7([M + H]⁺). i49

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.55 (m, 1 H), 4.21 (m, 1 H), 3.89 (m, 1H), 3.79-3.66 (m, 5 H), 3.54-3.51 (m, 3 H), 3.45- 3.32 (m, 3H), 3.11 (m,1 H), 2.97 (m, 2 H), 1.20 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI): m/z =326.2 ([M + H]⁺). i50

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.56 (m, 1 H), 4.24 (m, 3 H), 3.88 (m, 1H), 3.77 (m, 2 H), 3.67- 3.51 (m, 8 H), 3.40-3.37 (m, 1 H), 3.16 (m, 1H), 1.21 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI): m/z = 342.8 ([M +H]⁺). i51

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.56 (m, 1 H), 4.24 (m, 1 H), 3.87 (m, 5H), 3.68 (m, 1 H), 3.53 (m, 1 H), 3.35 (m, 1 H), 3.18 (m, 1 H), 2.01 (m,4 H), 1.21 (d, ³J_(H,H) = 6.9 Hz, 3 H). i52

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.53 (m, 1 H), 4.35 (m, 5 H), 4.20 (m, 1H), 3.87 (m, 1 H), 3.65 (m, 4H), 3.52 (m, 1 H), 3.37 (m, 1 H), 3.16 (m,1 H), 1.79 (m, 4 H), 1.20 (d, ³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI): m/z =340.2 ([M + H]⁺). i53

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.65 (m, 1 H), 4.55 (m, 1 H), 4.32 (m,1H), 4.22 (m, 2H) 3.98 (m, 1 H), 3.86 (m, 2 H), 3.63 (m, 2 H), 3.55 (m,1 H), 3.49- 3.34 (m, 4H), 3.17 (m, 1 H), 3.12 (m, 1 H), 1.21 (d,³J_(H,H) = 6.9 Hz, 3 H). MS (MALDI): m/z = 330.1 ([M + H]⁺). i82

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.67-4.53 (m, 1 H), 4.45-4.34 (m, 2 H),4.31-4.09 (m, 1 H), 3.88 (m, 1 H), 3.68 (m, 1 H), 3.55 (m, 3 H), 3.38(m, 1 H), 3.13 (m, 1 H), 2.55 (m, 2 H), 1.20 (d, ³J_(H,H) = 6.9 Hz, 3H),1.19 (d, ³J_(H,H) = 6.9 Hz, 6 H). MS (MALDI): m/z = 328.3 ([M + H]⁺).

Method 17:9-(4-chloro-6-(3,3-dimethylmorpholino)-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane(i54)

To a solution of 3,7-dioxa-9-azabicyclo[3.3.1]nonane (155 mg, 1.20 mmol,1.05 eq.) and N,N-diisopropylethylamine (0.42 mL, 2.40 mmol, 2.1 eq.) in1,4-dioxane (5 mL) a solution of i34 (300 mg, 1.14 mmol, 1 eq.) in1,4-dioxane (1 mL) is added. The resulting mixture is heated for 2 hours(70° C.). Then, ethyl acetate (20 mL) and saturated aqueous sodiumbisulfate (20 mL) are added. The phases are separated and the organiclayer is washed with saturated aqueous sodium bisulfate (2×20 mL). Theorganic layer is dried over anhydrous sodium sulfate and the solvent isremoved under reduced pressure. The crude mixture is purified byautomated flash chromatography (SiO₂, cyclohexane/ethyl acetate 2:1→0:1)to afford the title compound i54 as a colorless solid (178 mg, 44%). ¹HNMR (400 MHz, (CD₃)₂SO): δ4.32 (m, 2H), 4.05-3.98 (m, 4H), 3.77 (m, 4H),3.71 (m, 4H), 3.44 (m, 2H), 1.41 (s, 6H). MS (MALDI): m/z=356.3([M+H]⁺).

Method 17 is also used for the preparation of the following intermediatecompounds i55 to i64.

Reagent Structure NMR MS i55

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.36 (m, 2 H), 3.77-3.74 (m, 6 H), 3.55(m, 2 H), 3.44 (m, 2 H), 1.44 (s, 6H), 1.26 (d, ³J_(H,H) = 6.9 Hz, 6 H).MS (MALDI): m/z = 343.0 ([M + H]⁺). i56

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.52 (m, 1 H), 4.20 (m, 1 H), 3.90 (m, 2H), 3.77 (m, 4 H), 3.65 (m, 1 H), 3.51-3.41 (m, 5 H), 3.28 (s, 3H), 3.12(m, 1 H), 1.44 (s, 3 H), 1.43 (s, 3 H). i57

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.98 (m, 1 H), 4.35 (m, 1 H), 4.18 (m, 1H), 4.00 (m, 1 H), 3.87 (m, 1 H), 3.81-3.65 (m, 5 H), 3.51-3.35 (m, 5H), 3.21-3.04 (m, 1 H), 1.44 (s, 3H), 1.45 (s, 3H). MS (MALDI): m/z =344.2 ([M + H]⁺). i58

¹H NMR (400 MHz, (CD₃)₂SO): δ 3.77 (m, 4 H), 3.65 (m, 4 H), 3.44 (m,2H), 2.56 (m, 4 H), 1.64 (m, 1 H), 1.44 (s, 6 H), 0.44 (m, 2 H), 0.35(m, 2 H). MS (MALDI): m/z = 351.2 ([M + H]⁺). i59

¹H NMR (400 MHz, (CD₃)₂SO): δ 3.76 (m, 4 H), 3.68 (m, 4 H), 3.47-3.44(m, 4 H), 3.24 (m, 3 H), 2.52- 2.45 (m, 6 H), 1.44 (s, 6H). MS (MALDI):m/z = 369.0 ([M + H]⁺). i60

¹H NMR (400 MHz, (CD₃)₂SO): δ 5.56 (m, 1 H), 4.87 (m, 2H), 4.60 (m, 2H), 3.81 (m, 4 H), 3.48 (m, 2 H), 3.13 (s, 6 H). MS (MALDI): m/z = 301.1([M + H]⁺). i61

¹H NMR (400 MHz, (CD₃)₂SO): δ 5.46 (m, 1 H), 3.84-3.73 (m, 8 H), 3.49(m, 2 H), 2.21 (m, 1 H), 2.05 (m, 1 H), 1.46 (s, 3H). 1.45 (s, 3 H). MS(MALDI): m/z = 315.0 ([M + H]⁺). i62

¹H NMR (400 MHz, (CD₃)₂SO): δ 5.46 (m, 1 H), 3.84-3.73 (m, 8 H), 3.49(m, 2 H), 2.21 (m, 1 H), 2.05 (m, 1 H), 1.46 (s, 3H). 1.45 (s, 3 H). MS(MALDI): m/z = 315.0 ([M + H]⁺). i63

¹H NMR (400 MHz, (CD₃)₂SO): δ 5.11 (m, 1 H), 3.82 (m, 6 H), 3.47 (m, 4H), 1.99 (m, 2 H), 1.65 (m, 2 H), 1.46 (s, 6 H). MS (MALDI): m/z = 329.8([M + H]⁺). i64

¹H NMR (400 MHz, (CD₃)₂SO): δ 4.12 (m, 4 H), 3.79 (m, 4 H), 3.46 (m, 2H), 3.22 (m, 4 H), 1.46 (s, 6 H). MS (MALDI): m/z = 362.9 ([M + H]⁺).

Method 18: 4-(difluoromethyl(pyridin-2-amine (i65)

Palladium acetate (275 mg, 1.22 mmol, 0.05 eq.) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Sigma-Aldrich,product number 638064, 1.17 g, 2.45 mmol, 0.10 eq.) are dissolved in1,4-dioxane (10 mL) under nitrogen atmosphere, and the resulting mixtureis allowed to stir at room temperature for 45 minutes. This solution isthen added to a mixture of tert-butylcarbamate (Sigma, product number167398, 4.30 g, 36.7 mmol, 1.5 eq.), Cs₂CO₃ (15.9 g, 48.8 mmol, 2.0 eq.)and 2-chloro-4-difluoromethyl-pyridine (Manchester Organics, productnumber U15343, 4.00 g, 24.5 mmol, 1.0 eq.) in 1,4-dioxane (80 mL) undernitrogen atmosphere. The resulting reaction mixture is then heated at90° C. for 3 hours, during which it turned brownish. After this time,the mixture is allowed to cool to room temperature. It is then dilutedwith ethyl acetate, washed with an aqueous saturated solution ofammonium chloride (2×30 mL) and deionized water. The organic layer isdried over anhydrous sodium sulfate, filtered and the solvent isevaporated under reduced pressure. The brownish residue is mixed with 4M HCl in dioxane (50 mL, excess) and methanol (20 mL), and then heatedat 80° C. for 45 minutes. Deionized water is added and the aqueous layeris washed with ethyl acetate (3×). The aqueous layer is then basified topH=9, with solid sodium hydroxide. The aqueous layer is extracted withethyl acetate (3×). The combined organic layer is dried over anhydroussodium sulfate, filtered and concentrated to dryness under reducedpressure. The desired product i65 is obtained as a colorless solid,which is used in the next step without further purification (98% yield).¹H NMR (400 MHz, CDCl₃): δ8.16 (d, ²J_(H,H)=5.2 Hz, 1H), 6.74 (d,²J_(H,H)=4.8 Hz, 1H), 6.59 (s, 1H), 6.51 (t, ²J_(H,F)=56 Hz, 1H), 4.61(br s, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ−116.0 (s, 2 F).

Method 19: 5-bromo-4-(difluoromethyl)pyridin-2-amine (i66)

To a solution of compound i65 (3.00 g, 20.8 mmol, 1.0 eq.) intetrahydrofuran (60 mL) is added N-bromosuccinimide (3.89 g, 21.9 mmol,1.05 eq.) at 0° C. in an ice bath. The resulting mixture is stirredovernight, while it is allowed to warm up to room temperature. Ethylacetate is added and the organic layer is washed with aqueous sodiumcarbonate (8%). The organic layer is then separated and acidified withan aqueous 3 M HCl-solution. The aqueous layer is washed with ethylacetate (3×50 mL) and then basified to pH=10, with solid sodiumhydroxide. The aqueous layer is extracted with ethyl acetate (3×50 mL).The combined organic layer is dried over anhydrous sodium sulfate,filtered and concentrated to dryness under reduced pressure. The desiredproduct i66 is obtained as a brownish solid, which is used in the nextstep without further purification (79% yield). ¹H NMR (400 MHz, CDCl₃):δ8.20 (s, 1H), 6.75 (s, 1H), 6.71 (t, ²J_(H,F)=54 Hz, 1H); 4.62 (br s,2H); ¹⁹F NMR (376 MHz, CDCl₃): δ−118.9 (s, 2 F).

Method 20:N′-(5-bromo-4-(difluoromethyl)pyridin-2-yl)-N,N-dimethylformimidamide(i67)

To a solution of compound i66 (3.68 g, 16.5 mmol, 1.0 eq.) intetrahydrofuran (50 mL) is added N,N-dimethylformamide dimethyl acetal(Manchester Organics, product number 005030, 3.30 mL, 24.8 mmol, 1.5eq.) and the resulting mixture is stirred at 60° C. for 3 hours. Themixture is allowed to cool to room temperature and the solvent isevaporated under reduced pressure. The crude product is purified bycolumn chromatography on silica gel (cyclohexane/ethyl acetate 1:1) toafford the desired product i67 as a yellowish solid (82% yield). ¹H NMR(400 MHz, CDCl₃): δ8.43 (s, 1H), 8.34 (br s, 1H), 7.17 (s, 1H), 6.73 (t,²J_(H,F)=54 Hz, 1H), 3.12 (s, 3H), 3.10 (s, 3H); ¹⁹F NMR (376 MHz,CDCl₃): δ−118.6 (s, 2 F); MS (MALDI): m/z=278.5 ([M+H]⁺).

Method 21:N′-(4-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-N,N-dimethylformimidamide(i68)

To a 2 M solution of isopropylmagnesium chloride (Sigma, product number230111, 3.10 mL, 6.20 mmol, 1.15 eq.) in tetrahydrofuran (6 mL) isslowly added a solution of compound i67 (1.50 g, 5.39 mmol, 1.0 eq.) intetrahydrofuran (5 mL) at 0° C. The resulting brownish mixture isstirred at 0° C. for 45 minutes and then at room temperature for 15minutes. After this time, TLC monitoring (cyclohexane/ethyl acetate 1:1)showed complete consumption of starting material.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (ManchesterOrganics, product number W23343, 1.43 mL, 7.00 mmol, 1.3 eq.) is addedand the mixture is heated at 60° C. for 3 hours. The mixture is thenplaced in an Erlenmeyer flask, cooled to 0° C. with an ice bath andquenched with a 15% aqueous solution of ammonium chloride. The layersare separated and the aqueous layer is extracted with ethyl acetate(3×40 mL). The combined organic layers are dried over anhydrous sodiumsulfate, filtered and the solvent is evaporated under reduced pressure.Heptane is added and the organic layer is washed with a saturatedaqueous solution of sodium bicarbonate, dried over anhydrous sodiumsulfate, filtered and then concentrated to dryness under reducedpressure. The desired product i68 is obtained as a brownish oil, whichis used in the next step without further purification (94% yield).¹H NMR(400 MHz, CDCl₃): δ8.66 (s, 1H), 8.51 (s, 1H), 7.34-7.04 (m, 2H), 3.12(s, 3H), 3.12 (s, 3H), 1.34 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃): δ−115.6(s, 2 F); MS (MALDI): m/z=326.0 ([M+H]⁺).

Method 22: 4-(difluoromethyl(pyrimidin-2-amine (i69)

To a solution of ethyl vinyl ether (4.00 mL, 41.8 mmol, 1.0 eq.) in amixture of pyridine (4.10 mL, 50.7 mmol, 1.2 eq.) and dichloromethane(40 mL), is added dropwise a solution of 2,2-difluoroacetic anhydride(Manchester Organics, (product number L24754, 5.90 mL, 50.1 mmol, 1.2eq.) in dichloromethane (5 mL) at −70° C. in a dry ice/isopropanol bath.The resulting solution is allowed to warm up to room temperatureovernight. The mixture is then washed with deionized water, dried overanhydrous sodium sulfate, filtered and the solvent is evaporated underreduced pressure to afford an orange oil.

A solution of guanidine.HCl (Sigma, product number 50940, 4.80 g, 50.2mmol, 1.2 eq.) in ethanol (20 mL) is stirred at room temperature for 1hour. To this solution are added sodium hydroxide pellets (2.00 g, 50.0mmol, 1.2 eq.) in one portion. The resulting suspension is stirred atroom temperature overnight.

The resulting mixture is diluted with dichloromethane (20 mL) and addeddropwise over 1 hour. The resulting suspension is stirred at roomtemperature for 2 hours. Dichloromethane is evaporated under reducedpressure. Deionized water (25 mL) is added to the residue. The resultingmixture is stirred vigorously for 2 hours and is then allowed to standat room temperature overnight. The formed solid is filtered off, washedwith deionized water (2×) and heptane (1×) and then dried in vacuo. Thedesired product i69 is obtained as a colorless solid (65% yield). ¹H NMR(400 MHz, CDCl₃): δ8.43 (d, ²J_(H,H)=4.8 Hz, 1H), 7.02 (br s, 2H), 6.76(d, ²J_(H,H)=5.2 Hz, 1H), 6.67 (t, ²J_(H,F)=55 Hz, 1H); ¹⁹F NMR (376MHz, CDCl₃): δ−120.5 (s, 2 F).

Method 23: 5-bromo-4-(difluoromethyl)pyrimidin-2-amine (i70)

To a solution of compound i69 (3.00 g, 20.7 mmol, 1.0 eq.) intetrahydrofuran (90 mL) is added N-bromosuccinimide (3.86 g, 21.7 mmol,1.0 eq.) portionwise at 0° C. The reaction mixture is allowed to warm upto room temperature overnight. After this time, the solvent isevaporated under reduced pressure. The residue is taken up in ethylacetate (200 mL), washed with an aqueous saturated solution of sodiumcarbonate (4×), dried over anhydrous sodium sulfate, filtered and thenconcentrated to dryness under reduced pressure. The desired product i70is obtained as a yellowish solid, which is used in the next step withoutfurther purification (98% yield). ¹H NMR (400 MHz, (CD₃)₂SO): δ8.50 (s,1H), 7.30 (br s, 2H), 6.87 (t, ²J_(H,F)=53 Hz, 1H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−121.4 (s, 2 F).

Method 24: N-tert-butylcarboxylate-N-(5-bromo-4-(difluoromethyl)pyrimidin-2-yl)-carbamate (i71)

Compound i70 (4.35 g, 19.4 mmol, 1.0 eq.) and 4-(dimethylamino)pyridine(480 mg, 3.92 mmol, 0.20 eq.) are dissolved in tetrahydrofuran (50 mL).N,N-Diisopropylethylamine (7.50 mL, 42.1 mmol, 2.2 eq.) anddi-tert-butyl dicarbonate (9.33 g, 42.7 mmol, 2.2 eq.) are then added at0° C. and the resulting solution is allowed to warm up to roomtemperature overnight. The solvent is evaporated under reduced pressure.The crude product is purified by column chromatography on silica gel(cyclohexane/ethyl acetate 9:1→4:1) to afford the desired product i71 asa colorless solid (85% yield). ¹H NMR (400 MHz, CDCl₃): δ8.92 (s, 1H),6.73 (t, ²J_(H,F)=53 Hz, 1H), 1.47 (s, 18H); ¹⁹F NMR (376 MHz, CDCl₃):δ−120.4 (s, 2 F).

Method 25: methyl (4R,5R)-5-methyl-2-oxo-oxazolidine-4-carboxylate (i72)

Under nitrogen atmosphere, an oven-dried flask equipped with a refluxcondenser is charged with H-D-allo-threonine methyl ester.HCl (Bachem,product number 4044567, 2.00 g, 11.8 mmol, 1.0 eq.) and triphosgene(1.16 g, 3.91 mmol, 0.33 eq.). Tetrahydrofuran (20 mL) is added and theresulting mixture is heated to reflux for 1 hour. The mixture is thencooled down to room temperature, an aqueous NH₄Cl-solution (15%) isadded and the aqueous layer is extracted with dichloromethane (3×). Thecombined organic layer is dried over anhydrous sodium sulfate, filteredand the solvent is evaporated under reduced pressure. Purification bycolumn chromatography on silica gel (cyclohexane/ethyl acetate 1:1)gives the desired intermediate i72 as a colorless oil (66% yield). ¹HNMR (400 MHz, (CD₃)₂SO): δ7.98 (br s, 1H), 4.91-4.82 (m, 1H), 4.42 (d,³J_(H,H)=8.4 Hz, 1H), 3.71 (s, 3H), 1.17 (d, ³J_(H,H)=6.5 Hz, 3H).

Method 26:(4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-methyl-oxazolidin-2-one(i73)

To a solution of methyl (4R,5R)-5-methyl-2-oxo-oxazolidine-4-carboxylate(i72, 1.18 g, 7.41 mmol, 1.0 eq.) in tetrahydrofuran (15 mL) is addedLiBH₄ (200 mg, 9.18 mmol, 1.2 eq.) portionwise at 0° C. under nitrogenatmosphere. The reaction mixture is allowed to stir at 0° C. for 10minutes and then at room temperature for 1.5 hours. The reaction mixtureis quenched by addition of an aqueous saturated NH₄Cl-solution, stirredfor an additional hour at room temperature and then reduced to drynessunder reduced pressure. The resulting residue is triturated with amixture of ethyl acetate and dichloromethane (1:1), the solids arefiltered off, washed with ethyl acetate/dichloromethane (1:1) and thefiltrate is reduced to dryness under reduced pressure. The above residueis then dissolved in N,N-dimethylformamide (20 mL). Imidazole (581 mg,8.53 mmol, 1.2 eq.) and tert-butyldimethylsilyl chloride (1.23 g, 8.16mmol, 1.1 eq.) are added and the resulting reaction mixture is stirredat room temperature overnight. Brine is added and the aqueous layer isextracted with ethyl acetate (3×). The combined organic layer is driedover anhydrous sodium sulfate, filtered and the solvent is evaporated.Purification by column chromatography on silica gel (cyclohexane/ethylacetate 3:1) gives the desired intermediate i73 as a colorless solid(64% yield). ¹H NMR (400 MHz, (CD₃)₂SO): δ7.41 (br s, 1H), 4.72-4.63 (m,1H), 3.66-3.61 (m, 1H), 3.58 (br d, ³J_(H,H)=4.4 Hz, 2H), 1.32 (d,³J_(H,H)=6.6 Hz, 3H), 0.86 (s, 9H), 0.05 (d, ⁴J_(H,H)=2.6 Hz, 6H).

General Procedure 1:

Substituted monochloro-triazine or substituted monochloro-pyrimidine(1.0 eq.), compound i68 (1.1 eq.), potassium phosphate tribasic (2.0eq.) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II) (Sigma-Aldrich, productnumber 741825, 0.05 eq.) are charged in a flask. Under nitrogenatmosphere, 1,4-dioxane (30 volumes) and deionized water (1.5 volume)are added and the resulting mixture is then directly placed into an oilbath pre-heated at 95° C. The reaction mixture is stirred at thistemperature for 2 hours. A 5 M aqueous HCl-solution (20 eq.) is added.The resulting mixture is heated to 60° C. overnight. The pH of theresulting mixture is adjusted to 8-9 by addition of a 2 M aqueoussolution of sodium hydroxide, the mixture is then extracted with ethylacetate (3×20 volumes). The combined organic layers are dried overanhydrous sodium sulfate, filtered and the solvent is evaporated underreduced pressure. Purification by flash chromatography affords thedesired products of structure (I).

General Procedure 2:

Compound i71 (1.0 eq.),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (ManchesterOrganics, product number M23170, 1.5 eq.), potassium acetate (3.0 eq.)and [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)(Sigma-Aldrich, product number 697230, 0.099 eq.) are dissolved in1,4-dioxane (12.5 volumes) under nitrogen atmosphere. The resultingmixture is heated at 100° C. for 15 minutes (solution turned black). TLCmonitoring (cyclohexane/ethyl acetate 3:1) is used to show completeconsumption of starting material.

To the resulting mixture, substituted chloro-triazine or substitutedchloropyrimidine (1.1 eq.), an aqueous solution of potassium carbonate(2 M, 3.0 eq.) and a previously mixed solution of triphenylphosphine(0.12 eq.) and palladium acetate (0.04 eq.) in tetrahydrofuran (100volumes) are added. The resulting mixture is heated at 60° C. for 2hours and subsequently allowed to cool to room temperature.

A 5 M aqueous HCl-solution (20 eq.) is added. The resulting mixture isheated to 60° C. overnight. The pH of the resulting mixture is adjustedto 8-9 by addition of a 2 M aqueous solution of sodium hydroxide, themixture is then extracted with ethyl acetate (3×20 volumes). Thecombined organic layers are dried over anhydrous sodium sulfate,filtered and the solvent is evaporated under reduced pressure.Purification by flash chromatography affords the desired products.

Method 27: tert-butylN-tert-butoxycarbonyl-N-(5-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-yl)carbamate(i74)

Intermediate i71 (2.00 g, 4.71 mmol, 1.0 eq.), bis(pinacolato)diboron(1.80 g, 7.09 mmol, 1.5 eq.), KOAc (1.60 g, 16.3 mmol, 3.4 eq.) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (350 mg,478 μmol, 0.10 eq.) are mixed in 1,4-dioxane under nitrogen atmosphereand heated at 95° C. for 45 minutes. A pre-catalyst solution ofpalladium(II) acetate (43.0 mg, 192 μmol, 0.04 eq.) andtriphenylphosphine 148 mg, 564 μmol, 0.12 eq.) in tetrahydrofuran (2 mL)is also prepared and stirred at room temperature for 1 hour. Thissolution is then added to the cooled above solution at room temperature,followed by the addition of4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine i11 (1.65 g, 7.05 mmol,1.5 eq.) and aqueous K₂CO₃-solution (2.4 M, 5.90 mL, 14.2 mmol, 3.0eq.). The resulting mixture is heated at 55° C. overnight. After thistime, the mixture is poured onto an aqueous NH₄Cl-solution (15%) andextracted with ethyl acetate (3×). The combined organic layer is driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. Purification by column chromatography on silica gel(cyclohexane/ethyl acetate 1:0→4:1) gives product i74 as a colorlesssolid (36% yield). ¹H NMR (400 MHz, CDCl₃): δ9.57 (s, 1H), 7.55 (t,²J_(H,F)=54 Hz, 1H), 3.99-3.91 (m, 4H), 3.84-3.76 (m, 4H), 1.49 (s,18H); ¹⁹F NMR (376 MHz, CDCl₃): δ−121.0 (s, 2 F).

Method 28: (2R,3S)-3-amino-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol(i75)

D-allo-Threoninol (307 mg, 2.92 mmol, 1.0 eq.) is dissolved inN,N-dimethylformamide (3 mL) and imidazole (597 mg, 8.77 mmol, 3.0 eq.)is added. After 5 minutes, TBDPSCI (760 μL, 2.92 mmol, 1.0 eq.) is addedslowly and then the reaction mixture is stirred at room temperatureovernight. After this time, the solvent is evaporated under reducedpressure. The resulting residue is taken up in ethyl acetate and washedwith an aqueous saturated solution of sodium bicarbonate (1×) and brine(1×). The organic layer is dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. Purification by columnchromatography on silica gel (100% ethyl acetate) gives the desiredintermediate i75 as a colorless semisolid (50% yield). ¹H NMR (400 MHz,CDCl₃): δ7.70-7.61 (m, 4H), 7.47-7.36 (m, 6H), 3.82-3.73 (m, 1H), 3.69(d, ³J_(H,H)=5.8 Hz, 2H), 2.58 (q, ³J_(H,H)=5.8 Hz, 1H), 1.12 (d,³J_(H,H)=6.5 Hz, 3H), 1.07 (s, 9H).

Method 29:(4S,5R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-methyloxazolidin-2-one(i76)

Under nitrogen atmosphere, in an oven-dried flask equipped with a refluxcondenser, intermediate i75 (433 mg, 1.26 mmol, 1.0 eq.) andtriethylamine (440 μL, 3.15 mmol, 2.5 eq.) are dissolved indichloromethane (5 mL). At 0° C. in an ice-bath, triphosgene is thenadded (187 mg, 630 μmol, 0.5 eq.). The resulting mixture is stirredovernight, while it is allowed to warm up to room temperature. Thereaction is then quenched by addition of an aqueous NH₄Cl-solution (15%)and the aqueous mixture is extracted with dichloromethane (3×). Thecombined organic layer is dried over anhydrous sodium sulfate, filteredand the solvent is evaporated under reduced pressure. Purification bycolumn chromatography on silica gel (cyclohexane/ethyl acetate 1:0→3:2)gives the desired intermediate i76 as a colorless solid (73% yield). ¹HNMR (400 MHz, CDCl₃): δ7.66-7.61 (m, 4H), 7.47-7.38 (m, 6H), 4.99 (br s,1H), 4.82-4.74 (m, 1H), 3.85-3.79 (m, 1H), 3.68-3.65 (m, 2H), 1.34 (d,³J_(H,H)=6.7 Hz, 3H), 1.06 (s, 9H).

Method 30:(4S,5R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2,6-dibromopyrimidin-4-yl)-5-methyloxazolidin-2-one(i77)

Under nitrogen atmosphere,(4S,5R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-methyloxazolidin-2-one(i76, 681 mg, 1.84 mmol, 1.0 eq.) is dissolved in N,N-dimethylformamide(10 mL) and NaH (60% dispersion in mineral oil, 155 mg, 3.88 mmol, 2.1eq.) is added portionwise at 0° C., in an ice-bath. After 5 minutes,2,4,6-tribromopyrimidine (583 mg, 1.84 mmol, 1.0 eq.) is added. Theresulting mixture is stirred overnight, while it is allowed to warm upto room temperature. The reaction is then quenched by addition of anaqueous NH₄Cl-solution (15%) and the aqueous mixture is extracted withethyl acetate (3×). The combined organic layer is dried over anhydroussodium sulfate, filtered and the solvent is evaporated under reducedpressure. Purification by column chromatography on silica gel(cyclohexane/ethyl acetate 1:0→9:1) gives the desired product i77 as acolorless foam (55% yield). ¹H NMR (400 MHz, CDCl₃): δ8.25 (s, 1H),7.54-7.50 (m, 2H), 7.45-7.33 (m, 6H), 7.26-7.21 (m, 2H), 4.85 (quint,³J_(H,H)=6.9 Hz, 1H), 4.56-4.52 (m, 1H), 4.14 (dd, ²J_(H,H)=12 Hz,³J_(H,H)=2.8 Hz, 1H), 3.98 (dd, ²J_(H,H)=12 Hz, ³J_(H,H)=1.4 Hz, 1H),1.77 (d, ³J_(H,H)=6.5 Hz, 3H), 1.04 (s, 9H).

Method 31:(4S,5R)-3-(6-bromo-2-morpholinopyrimidin-4-yl)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-methyloxazolidin-2-one(i78)

Intermediate i77 (530 mg, 876 μmol, 1.0 eq.), morpholine (80.0 μL, 915μmol, 1.0 eq.) and N,N-diisopropylethylamine (200 μL, 1.15 mmol, 1.3eq.) are mixed in acetonitrile (7 mL) and the resulting mixture isheated at 85° C. overnight. Then, the mixture is allowed to cool down toroom temperature and the solvent is evaporated under reduced pressure.The desired product i78 is obtained as a colorless solid (12% yield)after purification by column chromatography on silica gel(cyclohexane/ethyl acetate 1:0→85:15).

¹H NMR (400 MHz, CDCl₃): δ7.70 (s, 1H), 7.59-7.55 (m, 2H), 7.46-7.31 (m,6H), 7.22-7.16 (m, 2H), 4.82 (quint, ³J_(H,H)=6.2 Hz, 1H), 4.50-4.44 (m,1H), 4.09 (dd, ²J_(H,H)=11 Hz, ³J_(H,H)=3.1 Hz, 1H), 3.88 (dd,²J_(H,H)=11 Hz, ³J_(H,H)=1.3 Hz, 1H), 3.69-3.33 (m, 8H), 1.74 (d,³J_(H,H)=6.6 Hz, 3H), 1.01 (s, 9H).

Method 32: (E)-4-ethoxy-1,1-difluoro-but-3-en-2-one (i83)

To a cooled (−70° C.) solution of pyridine (61.5 mL, 760.5 mmol, 1.2 eq)in dichloromethane (500 mL) is added ethyl vinyl ether (60 mL, 626.5mmol, 1 eq), followed by a solution a difluoroacetic anhydride (88.5 mL,760.5 mmol, 1.2 eq) in dichloromethane (75 mL). Then the mixture isslowly warmed to room temperature overnight. The mixture is transferredinto a separating funnel and the organic layer is washed with water(6×800 mL) until the pH of the aqueous layer becomes neutral. Theorganic layer is dried over sodium sulfate and solvent is removed underreduced pressure to afford the desired product i83 as an orange oil(76.7 g, 81%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (d, ³J_(H,H)=12.5 Hz,1H), 6.34 (t, ²J_(H,F)=53.6 Hz, 1H), 5.87 (d, ³J_(H,H)=12.5 Hz, 1H),4.14 (q, ³J_(H,H)=7.1 Hz, 2H), 1.28 (t, ³J_(H,H)=7.1 Hz, 3H); ¹⁹F {1H}NMR (400 MHz, DMSO-d₆): δ−127.39 (s, 2F).

Method 33: (E)-3-(difluoromethyl)-5-ethoxy-3-hydroxy-pent-4-enenitrile(i84)

To a cooled (−70° C.) solution of n-butyl lithium 2.5M (102.9 mL, 256.7mmol, 1 eq) in tetrahydrofuran (435 mL) is added acetonitrile (13.4 mL,256.7 mmol, 1 eq). A white suspension is formed and is stirred at −70°C. for 1 h30. A solution of (E)-4-ethoxy-1,1-difluoro-but-3-en-2-one(i83) (38.5 g, 256.7 mmol, 1 eq) in tetrahydrofuran (65 mL) is added tothe white suspension (mixture becomes an orange solution). The mixtureis stirred at −70° C. for 1 h and slowly warmed to room temperature.Water (400 mL) is added. Then ethyl acetate (600 mL) is added. Layersare separated and aqueous layer is extracted with ethyl acetate (3×600mL). Combined organic layers are dried over sodium sulfate and solventis evaporated under reduced pressure. Filtration on a short pad ofsilica gel, using a mixture of cyclohexane/ethyl acetate (3:1) aseluent, gives the desired product i84 as a dark orange oil (43.4 g,88%).¹H NMR (400 MHz, DMSO-d₆): δ 6.66 (d, ³J_(H,H)=12.8 Hz, 1H), 6.20(s, 1H), 5.79 (t, ²J_(H,F)=55.8 Hz, 1H), 4.75 (d, ³J_(H,H)=12.8 Hz, 1H),3.74 (q, ³J_(H,H)=7.0 Hz, 2H), 2.88 (d, ³J_(H,H)=16.8 Hz, 1H), 2.81 (d,³J_(H,H)=16.8 Hz, 1H), 1.21 (t, ³J_(H,H)=7.0 Hz, 1H); ¹⁹F {1H} NMR (400MHz, DMSO-d₆): δ −129.32 (d, ²J_(F,F)=311.2 Hz, 1F), −130.05 (d,²J_(F,F)=311.2 Hz, 1F).

Method 34: 4-(difluoromethyl(pyridin-2-amine (i65)

To a solution of(E)-3-(difluoromethyl)-5-ethoxy-3-hydroxy-pent-4-enenitrile (i84) (8.1g, 42.4 mmol, 1 eq) in acetic acid (80 mL) is addedO-methylhydroxylamine hydrochloride (Fluorochem, product number 078603)(10.6 g, 127.2 mmol, 3 eq). Mixture is stirred at 50° C. for 7 h. Thenreaction mixture is cooled down to room temperature and hydrobromic acidin acetic acid (33%) (14.2 mL, 84.8 mmol, 2 eq) is added. Reactionmixture is stirred at 90° C. overnight. Reaction mixture is degassed andplaced under nitrogen. Reaction mixture is maintained at roomtemperature with a water bath with ice while zinc powder (8.12 g, 127.2mmol, 3 eq) is added portionwise. Reaction mixture is stirred 3 h atroom temperature. Mixture is filtered over a short pad of celite and thecake is washed with ethyl acetate. Then the major part of the solvent isremoved under reduced pressure. 60 mL of aqueous ammonium hydroxide(28%) is added. Aqueous layer is extracted with dichloromethane (3×150mL). Combined organic layers are dried over sodium sulfate. Compound i65is recrystallized from dichloromethane and heptane as anti-solvent(solvent switch at the rotavap). Compound i65 is collected, as a lightyellow solid, by filtration (5.12 g, 84%).

Preparation of Compounds of the Invention

Example 1:4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine(1)

According to general procedure 1, compound 1 is obtained from startingmaterials i2 and i68 in 73% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ9.02 (s, 1H), 7.65 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (s, 1H), 4.85(br s, 2H), 3.89-3.79 (m, 8H), 3.77-3.72 (m, 8H); ¹⁹F NMR (376 MHz,CDCl₃): δ−115.9 (s, 2 F); MS (MALDI): m/z=393.9 ([M+H]⁺).

Example 2:4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine(2)

According to general procedure 2, compound 2 is obtained from startingmaterials i2 and i71 in 74% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ9.20 (s, 1H), 7.62 (t, ²J_(H,F)=54 Hz, 1H), 5.97 (br s, 2H),3.91-3.68 (m, 16H); ¹⁹F NMR (376 MHz, CDCl₃): δ−121.5 (s, 2 F); MS(MALDI): m/z=395.2 ([M+H]⁺).

Example 3:5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine(3)

According to general procedure 1, compound 3 is obtained from startingmaterials i1 and i68 in 75% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ9.04 (s, 1H), 7.71 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (s, 1H), 4.89(br s, 2H), 4.71-4.64 (m, 4H), 3.79-3.76 (m, 4H), 3.67-3.62 (m, 4H),2.09-1.98 (m, 8H); ¹⁹F NMR (376 MHz, CDCl₃): δ−115.4-(−117.3) (m, 2 F);MS (MALDI): m/z=446.3 ([M+H]⁺).

Example 4:5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine(4)

According to general procedure 1, compound 4 is obtained from startingmaterials i12 and i68 in 57% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.03 (s, 1H), 7.68 (m, 1H), 6.83 (s, 1H), 4.94 (br s, 2H),4.70-4.65 (m, 2H), 3.93-3.57 (m, 12H), 2.14-1.92 (m, 4H); ¹⁹F NMR (376MHz, CDCl₃): δ−116.0-(−116.2) (m, 2 F); MS (MALDI): m/z=420.6 ([M+H]⁺).

Example 5:5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine(5)

According to general procedure 2, compound 5 is obtained from startingmaterials i71 and i12 in 50% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.23 (s, 1H), 7.65 (t, ²J_(H,F)=54 Hz, 1H), 5.66 (br s,2H), 4.68 (m, 2H), 3.90-3.61 (m, 12H), 2.13-1.92 (4H); ¹⁹F NMR (376 MHz,CDCl₃): δ−120.4-(−121.5) (m, 2 F); MS (MALDI): m/z=420.9 ([M+H]⁺).

Example 6:5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine(6)

According to general procedure 1, compound 6 is obtained from startingmaterials i3 and i68 in 79% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ8.87 (s, 1H), 7.70 (t, ²J_(H,F)=55 Hz, 1H), 6.86 (s, 1H), 5.48(br s, 2H), 4.73-4.72 (m, 2H), 4.41-4.38 (m, 2H), 3.98 (dd,J_(H,H)=11.6, 3.8 Hz, 2H), 3.78 (d, J_(H,H)=12 Hz, 2H), 3.67 (dd,J_(H,H)=12, 3.2 Hz, 2H), 3.52 (td, J_(H,H)=12, 3.0 Hz, 2H), 3.27 (td,J_(H,H)=13, 3.8 Hz, 2H), 1.33 (d, ³J_(H,H)=6.8 Hz, 6H); ¹⁹F NMR (376MHz, CDCl₃): δ−115.4-(−116.2) (m, 2 F); MS (MALDI): m/z=421.9 ([M+H]⁺).

Example 7:5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine(7)

According to general procedure 2, compound 7 is obtained from startingmaterials i71 and i3 in 52% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ9.24 (s, 1H), 7.66 (t, ²J_(H,F)=54 Hz, 1H), 5.77 (br s, 2H),4.73 (br s, 2H), 4.45-4.32 (m, 2H), 3.98 (dd, J_(H,H)=12, 3.6 Hz, 2H),3.78 (d, J_(H,H)=12 Hz, 2H),3.67 (dd, J_(H,H)=11, 2.8 Hz, 2H), 3.52 (td,J_(H,H)=12, 2.8 Hz, 2H), 3.27 (td, J_(H,H)=13, 3.2 Hz, 2H), 1.33 (d,³J_(H,H)=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, CDCl₃): δ−120.5-(−122.7) (m, 2F); MS (MALDI): m/z=423.3 ([M+H]⁺).

Example 8:(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine(8)

According to general procedure 1, compound 8 is obtained from startingmaterials i13 and i68 in 47% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.03 (s, 1H), 7.70 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (s, 1H),4.78 (br s, 2H), 4.75 (m, 1H), 4.42-4.38 (m, 1H), 4.00-3.96 (m, 1H),3.84-3-366 (m, 10H), 3.55-3.50 (m, 1H), 3.30-3.25 (m, 1H), 1.33 (d,³J_(H,H)=6.8 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ−116.1-(−115.9) (m, 2F); MS (MALDI): m/z=408.9 ([M+H]⁺).

Example 9:(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine(9)

According to general procedure 2, compound 9 is obtained from startingmaterials i71 and i13 in 60% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.24 (s, 1H), 7.66 (t, ²J_(H,F)=54 Hz, 1H), 5.67 (br s,2H), 4.74 (m, 1H), 4.41-4.38 (m, 1H), 4.00-3.97 (m, 1H), 3.90-3.72 (m,9H), 3.68-3.36 (m, 1H), 3.56-3.49 (m, 1H), 3.32-3.25 (m, 1H), 1.33 (d,³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ−121.3-(−121.6) (m, 2F); MS (MALDI): m/z=409.4 ([M+H]⁺).

Example 10:5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine(10)

According to general procedure 1, compound 10 is obtained from startingmaterials i18 and i68 in 42% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.04 (s, 1H), 7.69 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (s, 1H),4.85 (br s, 2H), 4.71-4.65 (m, 3H), 4.42-4.39 (m, 1H), 3.98-3.95 (m,1H), 3.79-3.76 (m, 3H), 3.70-3.65 (m, 3H), 3.56-3.53 (m, 1H), 3.30-3.27(m, 1H), 2.10-1.99 (m, 4H), 1.33 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃):δ−115.9-(−116.2) (m, 2 F); MS (MALDI): m/z=434.2 ([M+H]⁺).

Example 11:5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine(11)

According to general procedure 2, compound 11 is obtained from startingmaterials i71 and i18 in 46% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.25 (s, 1H), 7.68 (t, ²J_(H,F)=55 Hz, 1H), 5.81 (br s,2H), 4.71-4.65 (m, 3H), 4.42-4.38 (m, 1H), 4.00-3.96 (m, 1H), 3.81-3.60(m, 6H), 3.55-3.50 (m, 1H), 3.31-3.24 (m, 1H), 2.11-2.00 (m, 4H),1.37-1.28 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ−121.5-(−121.7) (m, 2 F);MS (MALDI): m/z=434.6 ([M+H]⁺).

Example 12:4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine(12)

According to general procedure 1, compound 12 is obtained from startingmaterials i68 and i14 in 86% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.85 (s, 1H), 7.74 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (s,2H), 6.75 (s, 1H), 3.82-3.70 (m, 8H), 3.69-3.60 (m, 4H), 2.88-2.80 (m,4H) ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.4 (s, 2 F); MS (MALDI): m/z=393.8([M+H]⁺).

Example 13:4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine(13)

According to general procedure 2, compound 13 is obtained from startingmaterials i71 and i14 in 55% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.23 (s, 1H), 7.64 (t, ²J_(H,F)=55 Hz, 1H), 5.60 (br s,2H), 3.83-3.75 (m, 12H), 2.94-2.88 (m, 4H); ¹⁹F NMR (376 MHz, CDCl₃):δ−111.4 (s, 2 F); MS (MALDI): m/z=395.1 ([M+H]⁺).

Example 14:(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine(14)

According to general procedure 1, compound 14 is obtained from startingmaterials i21 and i68 in 47% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.02 (s, 1H), 7.67 (t, ²J_(H,F)=56 Hz, 1H), 6.84 (s, 1H),4.90 (br s, 2H), 4.74 (s, 1H), 4.40 (d, J_(H,H)=16 Hz, 1H), 3.98 (dd,J_(H,H)=4.0 Hz, 12 Hz, 1H), 3.91 (m, 4H), 3.78 (d, J_(H,H)=12 Hz, 1H),3.68 (dd, J_(H,H)=4.0, 12 Hz, 1H), 3.56 (t, J_(H,H)=4.0 Hz, 1H), 3.26(dt, J_(H,H)=4.0, 12 Hz, 1H), 2.99 (t, J_(H,H)=4.0 Hz, 4H), 1.32 (d,J_(H,H)=8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ−115.9 (s, 2 F); MS(MALDI): m/z=407.2 ([M+H]⁺).

Example 15:(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine(15)

According to general procedure 2, compound 15 is obtained from startingmaterials i71 and i21 in 30% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.24 (s, 1H), 7.66 (t, ²J_(H,F)=56 Hz, 1H), 5.69 (br s,2H), 4.74 (s, 1H), 4.40 (d, J_(H,H)=16 Hz, 1H), 4.38 (dd, J_(H,H)=4.0,12 Hz, 1H), 3.83 (m, 4H), 3.78 (d, J_(H,H)=12 Hz, 1H), 3.68 (dd,J_(H,H)=4.0, 12 Hz, 1H), 3.54 (dt, J_(H,H)=4.0, 12 Hz, 1H), 3.28 (dt,J_(H,H)=4.0, 12 Hz, 1H), 2.92 (t, J_(H,H)=8.0 Hz, 4H), 1.33 (t,J_(H,H)=8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ−121.4 (s, 2 F); MS(MALDI): m/z=408.7 ([M+H]⁺).

Example 16:4-(difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine(16)

According to general procedure 1, compound 16 is obtained from startingmaterials i22 and i68 in 73% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ8.31 (s, 1H), 7.30 (t, ²J_(H,F)=55 Hz, 1H), 6.85 (s, 1H),6.04 (s, 1H), 4.73 (br s, 2H), 3.81-3.72 (m, 12H), 3.65-3.59 (m, 4H);¹⁹F NMR (376 MHz, CDCl₃): δ−115.1 (s, 2 F); MS (MALDI): m/z=394.3([M+H]⁺).

Example 17:4′-(difluoromethyl)-2,6-dimorpholino-[4,5′-bipyrimidin]-2′-amine (17)

According to general procedure 2, compound 17 is obtained from startingmaterials i71 and i22 in 7% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ8.60 (s, 1H), 7.11 (t, ²J_(H,F)=55 Hz, 1H), 6.02 (s, 1H), 5.46(br s, 2H), 3.80-3.74 (m, 12H), 3.64-3.60 (m, 4H); ¹⁹F NMR (376 MHz,CDCl₃): δ−119.5 (s, 2 F); MS (MALDI): m/z=394.3 ([M+H]⁺).

Example 18:4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine(18)

According to general procedure 1, compound 18 is obtained from startingmaterials i23 and i68 in 89% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ8.94 (s, 1H), 7.61 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (s, 1H),5.50 (s, 1H), 4.74 (br s, 2H), 3.82-3.78 (m, 8H), 3.61-3.57 (m, 8H); ¹⁹FNMR (376 MHz, CDCl₃): δ−115.4 (s, 2 F); MS (MALDI): m/z=393.3 ([M+H]⁺).

Example 19:4′-(difluoromethyl)-4,6-dimorpholino[2,5′-bipyrimidin]-2-amine (19)

According to general procedure 2, compound 19 is obtained from startingmaterials i71 and i23 in 7% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ9.16 (s, 1H), 7.58 (t, ²J_(H,F)=55 Hz, 1H), 5.75 (br s, 2H),5.50 (s, 1H), 3.82-3.79 (m, 8H), 3.61-3.58 (m, 8H); ¹⁹F NMR (376 MHz,CDCl₃): δ−121.1 (s, 2 F); MS (MALDI): m/z=395.3 ([M+H]⁺).

Example 20:4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-pyridin-2-amine(20)

According to general procedure 1, compound 20 is obtained from startingmaterials i15 and i68 in 77% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.02 (s, 1H), 7.65 (t, J=55 Hz, 1H), 6.84 (s, 1H), 4.83(br s, 2H), 4.23-4.07 (m, 4H), 3.90-3.79 (m, 4H), 3.79-3.71 (m, 4H),2.71-2.62 (m, 4H); ¹⁹F NMR (376 MHz, CDCl₃): δ−116.0 (s, 2 F); MS(MALDI): m/z=410.3 ([M+H]⁺).

Example 21:4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-pyrimidin-2-amine(21)

According to general procedure 2, compound 21 is obtained from startingmaterials i71 and i15 in 70% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.21 (s, 1H), 7.60 (t, ²J_(H,F)=54 Hz, 1H), 5.90 (br s,2H), 4.22-4.06 (m, 4H), 3.91-3.78 (m, 4H), 3.78-3.71 (m, 4H), 2.71-2.62(m, 4H); ¹⁹F NMR (376 MHz, CDCl₃): δ−120.5-(−121.5) (m, 2 F); MS(MALDI): m/z=411.2 ([M+H]⁺).

Example 22:5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine(22)

According to general procedure 1, compound 22 is obtained from startingmaterials i24 and i68 in 61% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.34 (s, 1H), 7.55 (t, ²J_(H,F)=55 Hz, 1H), 6.76 (s,1H), 6.60 (br s, 2H), 6.36 (s, 1H), 4.64-4.47 (m, 4H), 3.67-3.49 (m,4H), 3.56-3.49 (m, 4H), 1.98-1.79 (m, 8H); ¹⁹F NMR (376 MHz, (CD₃)₂SO):δ−114.9-(−115.2) (m, 2 F); MS (MALDI): m/z=445.3 ([M+H]⁺).

Example 23:5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine(23)

According to general procedure 1, compound 23 is obtained from startingmaterials i29 and i68 in 54% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ8.30 (s, 1H), 7.30 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (s, 1H),6.04 (s, 1H), 4.85 (br s, 2H), 4.62 (br s, 2H), 3.82-3.74 (m, 6H),3.65-3.56 (m, 6H), 2.09-2.00 (m, 2H), 2.00-1.91 (m, 2H);

¹⁹F NMR (376 MHz, CDCl₃): δ−115.2-(−116.2) (m, 2 F); MS (MALDI):m/z=419.0 ([M+H]⁺).

Example 24:2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′-(difluoromethyl)-6-morpholino-[4,5′-bipyrimidin]-2′-amine(24)

According to general procedure 2, compound 24 is obtained from startingmaterials i29 and i71 in 72% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.71 (s, 1H), 7.35 (s, 2H), 7.32 (t, ²J_(H,F)=54 Hz,1H), 6.45 (s, 1H), 4.54 (br s, 2H), 3.71-3.50 (m, 12H), 1.95-1.78 (m,4H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−119.2 (s, 2 F); MS (MALDI):m/z=420.6 ([M+H]⁺).

Example 25:5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine(25)

According to general procedure 1, compound 25 is obtained from startingmaterials i25 and i68 in 57% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.31 (s, 1H), 7.52 (t, ²J_(H,F)=55 Hz, 1H), 6.76 (s,1H), 6.59 (br s, 2H), 6.30 (s, 1H), 4.60-4.50 (m, 1H), 4.44-4.33 (m,1H), 4.24-4.15 (m, 1H), 4.12-4.04 (m, 1H), 3.94-3.83 (m, 2H), 3.74-3.64(m, 2H), 3.59-3.51 (m, 2H), 3.45-3.35 (m, 2H), 3.14-3.02 (m, 2H), 1.18(t, ³J_(H,H)=7.2 Hz, 6H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−113.7-(−115.9)(m, 2 F); MS (MALDI): m/z=421.1 ([M+H]⁺).

Example 26:4′-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5′-bipyrimidin]-2′-amine(26)

According to general procedure 2, compound 26 is obtained from startingmaterials i25 and i71 in 56% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ8.60 (s, 1H), 7.14 (t, ²J_(H,F)=54 Hz, 1H), 5.98 (s, 1H),5.48 (br s, 2H), 4.71-4.62 (m, 1H), 4.34-4.23 (m, 2H), 4.08-3.92 (m,3H), 3.83-3.65 (m, 4H), 3.61-3.49 (m, 2H), 3.25 (dt, ²J_(H,H)=13 Hz,³J_(H,H)=3.6 Hz, 2H), 1.33-1.27 (m, 6H); ¹⁹F NMR (376 MHz, CDCl₃):δ−119.5 (s, 1 F), 119.7 (m, 1 F); MS (MALDI): m/z=423.0 ([M+H]⁺).

Example 27:(S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine(27)

According to general procedure 1, compound 27 is obtained from startingmaterials i30 and i68 in 74% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ8.31 (s, 1H), 7.30 (t, ²J_(H,F)=55 Hz, 1H), 6.85 (s, 1H),6.02 (s, 1H), 4.75 (br s, 2H), 4.35-4.25 (m, 1H), 4.06-3.96 (m, 2H),3.83-3.69 (m, 10H), 3.58 (dt, ²J_(H,H)=12 Hz, ³J_(H,H)=3.2 Hz, 1H), 3.25(dt, ²J_(H,H)=13 Hz, ³J_(H,H)=3.8 Hz, 1H), 1.31 (d, ³J_(H,H)=6.8 Hz,3H); ¹⁹F NMR (376 MHz, CDCl₃): δ−114.9-(−115.0) (m, 2 F); MS (MALDI):m/z=407.1 ([M+H]⁺).

Example 28:(S)-4′-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5′-bipyrimidin]-2′-amine(28)

According to general procedure 2, compound 28 is obtained from startingmaterials i30 and i71 in 53% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ8.60 (s, 1H), 7.13 (t, ²J_(H,F)=54 Hz, 1H), 6.01 (s, 1H),5.47 (br s, 2H), 4.71-4.63 (m, 1H), 4.31 (dd, ²J_(H,H)=14 Hz,³J_(H,H)=2.4 Hz, 1H), 3.97 (dd, ²J_(H,H)=11 Hz, ³J_(H,H)=3.4 Hz, 1H),3.79 (t, ³J_(H,H)=4.6 Hz, 4H), 3.72-3.66 (m, 2H), 3.65-3.58 (m, 3H),3.58-3.50 (m, 2H), 3.30-3.21 (m, 1H), 1.30 (d, ³J_(H,H)=6.8 Hz, 3H); ¹⁹FNMR (376 MHz, CDCl₃): δ−119.7 (br s, 2 F); MS (MALDI): m/z=408.9([M+H]⁺).

Example 29:5-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine29

According to general procedure 1, compound 29 is obtained from startingmaterials i68 and i81 in 89% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.03 (s, 1H), 7.69 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (s, 1H),4.85 (br s, 2H), 4.50-4.24 (m, 8H), 3.28-3.12 (m, 4H), 1.94 (br s, 4H),1.86-1.71 (m, 4H); ¹⁹F NMR (376 MHz, CDCl₃): δ−115.1-(−117.2) (m, 2 F);MS (MALDI): m/z=446.3 ([M+H]⁺).

Example 30:5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine30

According to general procedure 1, compound 30 is obtained from startingmaterials i68 and i80 in 63% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.86 (s, 1H), 7.71 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s,2H), 6.76 (s, 1H), 3.81-3.56 (m, 12H), 1.14 (s, 12H); MS (MALDI):m/z=451.2 ([M+H]⁺).

Example 31:(S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine(31)

According to general procedure 1, compound 31 is obtained from startingmaterials i28 and i68 in 58% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.31 (s, 1H), 7.52 (t, ²J_(H,F)=55 Hz, 1H), 6.74 (s,1H), 6.59 (br s, 2H), 6.35 (s, 1H), 4.59-4.51 (m, 1H), 4.22-4.14 (m,1H), 3.91-3.84 (m, 1H), 3.72-3.50 (m, 10H), 3.44-3.35 (m, 1H), 3.14-3.03(m, 1H), 1.16 (d, ³J_(H,H)=6.7 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO):δ−113.7-(−115.3) (m, 2 F); MS (MALDI): m/z=407.1 ([M+H]⁺).

Example 32:(S)-4′-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5′-bipyrimidin]-2′-amine(32)

According to general procedure 2, compound 32 is obtained from startingmaterials i28 and i71 in 63% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ8.60 (s, 1H), 7.13 (t, ²J_(H,F)=54 Hz, 1H), 5.99 (s, 1H),5.46 (br s, 2H), 4.34-4.25 (m, 1H), 4.06-3.97 (m, 2H), 3.82-3.68 (m,10H), 3.58 (dt, ²J_(H,H)=12 Hz, ³J_(H,H)=3.2 Hz, 1H), 3.26 (dt,²J_(H,H)=13 Hz, ³J_(H,H)=3.7 Hz, 1H), 1.31 (d, ³J_(H,H)=6.8 Hz, 3H); ¹⁹FNMR (376 MHz, (CD₃)₂SO): δ−119.5 (s, 2 F); MS (MALDI): m/z=408.7([M+H]⁺).

Example 33:4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine33

According to general procedure 1, compound 33 is obtained from startingmaterials i68 and i82 in 71% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.74 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 4.71-4.62 (m, 1H), 4.45-4.34 (m, 2H), 4.31-4.09 (m,1H), 3.90 (m, 1H), 3.71 (m, 1H), 3.55 (m, 3H), 3.38 (m, 1H), 3.13 (m,1H), 2.55 (m, 2H), 1.20 (d, ³J_(H,H)=6.9 Hz, 3H), 1.19 (d, ³J_(H,H)=6.9Hz, 6H); MS (MALDI): m/z=436.1 ([M+H]⁺).

Example 34:5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine34

According to general procedure 1, compound 34 is obtained from startingmaterials i68 and i79 in 75% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.86 (s, 1H), 7.71 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 4.64-4.46 (m, 4H), 3.60-3.48 (m, 4H), 2.63 (m, 4H),1.14 (m, 12H); MS (MALDI): m/z=450.0 ([M+H]⁺).

Example 35:4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one(35)

According to general procedure 1, compound 35 is obtained from startingmaterials i31 and i68 in 10% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃): δ9.08 (s, 1H), 7.96 (t, ²J_(H,F)=56 Hz, 1H), 6.86 (s, 1H),4.98 (br s, 2H), 4.35 (s, 2H), 4.07-4.00 (m, 4H), 3.95 (br s, 2H), 3.90(br s, 2H), 3.78 (br s, 4H); ¹⁹F NMR (376 MHz, CDCl₃): δ−117.4 (s, 2 F).

Example 36:4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one(36)

According to general procedure 2, compound 36 is obtained from startingmaterials i31 and i71 in 6% yield as a colorless solid. ¹H NMR (400 MHz,(CD₃)₂SO): δ9.22 (s, 1H), 8.10 (t, ²J_(H,F)=56 Hz, 1H), 7.97 (br s, 2H),4.28 (s, 2H), 3.98 (s, 4H), 3.90 (br s, 2H), 3.81 (br s, 2H), 3.70 (brs, 4H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−121.1 (s, 2 F); MS (MALDI):m/z=408.7 ([M+H]⁺).

Example 37:5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(37)

According to general procedure 1, compound 37 is obtained from startingmaterials i7 and i68 in 39% yield as a colorless solid. ¹H NMR (400 MHz,(CD₃)₂SO): δ8.85 (s, 1H), 7.68 (t, ³J_(H,F)=55 Hz, 1H), 6.87 (br s, 2H),6.74 (s, 1H), 4.51 (br s, 2H), 4.45 (br s, 2H), 4.07-3.93 (m, 8H),3.79-3.67 (m, 8H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.8 (s, 2 F); MS(MALDI): m/z=478.1 ([M+H]⁺).

Example 38:4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine(38)

According to general procedure 1, compound 38 is obtained from startingmaterials i35 and i68 in 67% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.73 (t, ³J_(H,F)=55 Hz, 1H), 6.87 (br s,2H), 6.75 (s, 1H), 4.70-4.54 (m, 2H), 4.53-4.43 (m, 2H), 4.05-3.97 (m,4H), 3.79-3.67 (m, 4H), 3.63-3.55 (m, 4H) 2.00-1.83 (m, 4H);

¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.8 (s, 1 F), −115.9 (s, 1 F); MS(MALDI): m/z=462.1 ([M+H]⁺).

Example 39:5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(39)

According to general procedure 1, compound 39 is obtained from startingmaterials i4 and i68 in 28% yield as a colorless solid. ¹H NMR (400 MHz,(CD₃)₂SO): δ8.78 (s, 1H), 7.70 (t, ²J_(H,F)=55 Hz, 1H), 6.82 (br s, 2H),6.77 (s, 1H), 3.87-3.75 (m, 8H), 3.45 (br s, 4H), 1.49 (s, 12H); ¹⁹F NMR(376 MHz, (CD₃)₂SO): δ−114.9-(−115.1) (m, 2 F); MS (MALDI): m/z=450.1([M+H]⁺).

Example 40:5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl(pyridin-2-amine(40)

According to general procedure 1, compound 40 is obtained from startingmaterials i6 and i68 in 42% yield as a colorless solid. ¹H NMR (400 MHz,(CD₃)₂SO): δ8.90 (s, 1H), 7.82 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s, 2H),6.77 (s, 1H), 4.59-4.43 (m, 4H), 3.82-3.73 (m, 4H), 3.60-3.51 (m, 4H),1.29 (d, ²J_(H,H)=6.9 Hz, 12H); ¹⁹F NMR (376 MHz, (CD₃)₂SO):δ−114.9-(−115.0) (m, 2 F); MS (MALDI): m/z=450.2 ([M+H]⁺).

Example 41:5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl(pyridin-2-amine(41)

According to general procedure 1, compound 41 is obtained from startingmaterials i5 and i68 in 98% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ9.04 (s, 1H), 7.70 (t, ²J_(H,F)=52.0 Hz, 1H), 6.84 (s, 1H),4.88 (br s, 2H), 4.77-4.72 (m, 2H), 4.41 (d, ²J_(H,H)=12.0 Hz, 2H), 3.98(dd, ²J_(H,H)=12.0 Hz, ³J_(H,H)=4.0 Hz, 2H), 3.78 (d, ²J_(H,H)=12.0 Hz,2H), 3.68 (dd, ²J_(H,H)=12.0 Hz, ³J_(H,H)=4.0 Hz, 2H), 3.53 (dt,²J_(H,H)=12.0 Hz, ³J_(H,H)=4.0 Hz, 2H), 3.28 (dt, ²J_(H,H)=12.0 Hz,³J_(H,H)=4.0 Hz, 2H), 1.33 (d, ²J_(H,H)=8.0 Hz, 6H); ¹⁹F NMR (376 MHz,CDCl₃): δ−115.9 (s, 1 F), −116.0 (s, 1 F); MS (MALDI): m/z=421.7([M+H]⁺).

Example 42:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine(42)

According to general procedure 1, compound 42 is obtained from startingmaterials i16 and i68 in 35% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.83 (s, 1H), 7.73 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s,2H), 6.76 (s, 1H), 3.85-3.76 (m, 4H), 3.76-3.63 (m, 8H), 3.45 (br s,2H), 1.49 (s, 6H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.0/−116.3 (s, 2 F);MS (MALDI): m/z=423.2 ([M+H]⁺).

Example 43:5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(43)

According to general procedure 1, compound 43 is obtained from startingmaterials i33 and i68 in 43% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ9.01 (s, 2H), 7.81 (t, ²J_(H,F)=55 Hz, 2H), 7.00 (br s,4H), 6.82 (s, 2H), 4.78-4.66 (m, 1H), 4.44-4.35 (m, 1H), 4.01-3.91 (m,1H), 3.81-3.72 (m, 1H), 3.65-3.58 (m, 1H), 3.52-3.42 (m, 1H), 3.38-3.23(m, 1H) 1.30 (d, ³J_(H,H)=6.7 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO):δ−114.3-(−117.2) (m, 4 F); MS (MALDI): m/z=465.1 ([M+H]⁺).

Example 44:4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(44)

According to general procedure 1, compound 44 is obtained from startingmaterials i37 and i68 in 75% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.89 (s, 1H), 7.79 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 4.65 (br s, 1H), 4.50 (br s, 2H), 4.37-4.25 (m, 1H),3.93 (dd, ³J_(H,H)=11 Hz, ³J_(H,H)=3.2 Hz, 1H), 3.79-3.67 (m, 3H),3.59-3.51 (m, 3H), 3.45-3.36 (m, 1H), 3.22-3.11 (m, 1H), 1.30 (d,³J_(H,H)=6.7 Hz, 6H), 1.24 (d, ³J_(H,H)=6.7 Hz, 3H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.0 (br s, 2 F); MS (MALDI): m/z=436.1 ([M+H]⁺).

Example 45:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(45)

According to general procedure 1, compound 45 is obtained from startingmaterials i38 and i68 in 71% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.84 (s, 1H), 7.74 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 4.58 (br s, 1H), 4.31-4.19 (m, 1H), 3.93 (dd,²J_(H,H)=12 Hz, ³J_(H,H)=3.9 Hz, 1H), 3.84-3.81 (m, 4H), 3.76-3.69 (m,1H), 3.58 (dd, ²J_(H,H)=11 Hz, ³J_(H,H)=3.2 Hz, 1H), 3.46-3.38 (m, 3H),3.23-3.13 (m, 1H), 1.50 (br s, 6H), 1.23 (d, ³J_(H,H)=6.7 Hz, 3H); ¹⁹FNMR (376 MHz, (CD₃)₂SO): δ−114.8-(−115.5) (m, 2 F); MS (MALDI):m/z=436.0 ([M+H]⁺).

Example 46:4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(46)

According to general procedure 1, compound 46 is obtained from startingmaterials i39 and i68 in 67% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.77 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s,2H), 6.76 (s, 1H), 4.67 (br s, 2H), 4.44-4.24 (m, 2H), 3.96-3.83 (m,3H), 3.75-3.63 (m, 2H), 3.60-3.36 (m, 5H), 3.31 (s, 3H), 3.21-3.04 (m,2H), 1.23 (d, ³J_(H,H)=6.7 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.0(br s, 2 F); MS (MALDI): m/z=452.3 ([M+H]⁺).

Example 47:4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(47)

According to general procedure 1, compound 47 is obtained from startingmaterials i36 and i68 in 85% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.86 (s, 1H), 7.72 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s,2H), 6.75 (s, 1H), 4.64 (br s, 1H), 4.53-4.42 (m, 2H), 4.37-4.25 (m,1H), 4.05-3.96 (m, 4H), 3.92-3.84 (m, 1H), 3.77-3.66 (m, 5H), 3.60-3.52(m, 1H), 3.44-3.35 (m, 1H), 3.22-3.10 (m, 1H), 1.23 (d, ³J_(H,H)=6.7 Hz,3H);

¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−114.9-(−117.1) (m, 2 F); MS (MALDI):m/z=450.0 ([M+H]⁺).

Example 48:(4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one(48)

tert-ButylN-tert-butoxycarbonyl-N-(5-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-yl(carbamate(i74, 350 mg, 643 μmol, 1.0 eq.),(4S,5R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyloxazolidin-2-one(i73, 174 mg, 709 μmol, 1.1 eq.),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22.3 mg, 38.5 μmol,0.06 eq.), cesium carbonate (419 mg, 1.29 mmol, 2.0 eq.) andpalladium(II) acetate (5.80 mg, 25.8 μmol, 0.04 eq.) are mixed in1,4-dioxane (5 mL) under nitrogen atmosphere and heated at 95° C. for 2hours. After this time, the reaction mixture is allowed to cool down toroom temperature, deionized H₂O is added, and the aqueous layer isseparated and extracted with ethyl acetate (3×). The combined organiclayer is dried over anhydrous sodium sulfate, filtered and the solventis evaporated under reduced pressure.

The above residue is dissolved in tetrahydrofuran (5 mL) and aqueous HCl(3M, 2.00 mL, 6.00 mmol, 14 eq.) is added. The resulting mixture isheated at 60° C. overnight. Then, aqueous saturated sodium bicarbonateand ethyl acetate are added. The aqueous layer is separated andextracted with ethyl acetate (3×). The combined organic layer is driedover anhydrous sodium sulfate, filtered and concentrated and reducedpressure. Purification by column chromatography on silica gel (100%ethyl acetate) gives product 48 as a colorless solid (55% yield).

¹H NMR (400 MHz, (CD₃)₂SO): δ9.23 (s, 1H), 8.23 (t, ²J_(H,F)=54 Hz, 1H),7.81-7.53 (m, 2H), 4.99 (t, ²J_(H,F)=5.2 Hz, 1H), 4.82 (q, ²J_(H,F)=6.5Hz, 1H), 4.56-4.51 (m, 1H), 4.03-3.97 (m, 1H), 3.95-3.60 (m, 9H), 1.50(d, ²J_(H,F)=6.5 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−121.3 (s, 1 F),−121.4 (s, 1 F); MS (MALDI): m/z=439.1 ([M+H]⁺).

Example 49:(4S,5R)-3-[6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-pyrimidin-4-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one(49)

tert-ButylN-[5-bromo-4-(difluoromethyl)pyrimidin-2-yl]-N-tert-butoxycarbonyl-carbamate(i71, 44.0 mg, 104 μmol, 1.0 eq.), bis(pinacolato)diboron (27.0 g, 106μmol, 1.0 eq.), KOAc (31.0 mg, 316 μmol, 3.0 eq.) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (7.70 mg,10.5 μmol, 0.10 eq.) are mixed in 1,4-dioxane (2 mL) under nitrogenatmosphere and heated at 95° C. for 55 minutes.

After this time, the above reaction mixture is allowed to cool down toroom temperature. Then, compound i78 (64.0 mg, 105 μmol, 1.0 eq.),potassium phosphate tribasic (44.0 mg, 207 μmol, 2.0 eq.),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II) (Sigma-Aldrich, productnumber 741825, 8.20 mg, 10.4 μmol, 0.10 eq.), 1,4-dioxane (2 mL) anddeionized H₂O (0.5 mL) are added and the resulting dark mixture isplaced in a pre-heated oil bath at 95° C. for 16 hours. After this time,aqueous saturated sodium bicarbonate and dichloromethane are added. Theaqueous layer is separated and extracted with dichloromethane (3×). Thecombined organic layer is dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. This intermediate is purifiedby column chromatography on silica gel (cyclohexane/ethyl acetate1:0→1:1) to afford a colorless semisolid.

The semisolid obtained above is then dissolved in tetrahydrofuran (2 mL)and a solution of HCl in dioxane (1 M, 100 μL, 100 μmol, 1.0 eq) isadded. The resulting mixture is stirred at room temperature overnight.After this time, the solvents are evaporated and the residue is dried invacuo.

The above salt is then dissolved in tetrahydrofuran (2 mL) and asolution of tetrabutylammonium fluoride hydrate in tetrahydrofuran (1 M,100 μL, 100 μmol, 1.0 eq.) is added. The reaction mixture is allowed tostir at room temperature for 2 days. After this time, aqueous saturatedsodium bicarbonate is added and the product is extracted with ethylacetate (3×). The combined organic layer is washed with an aqueoussaturated NH₄Cl-solution (3×), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford a yellowishsolid. This solid is triturated with diethyl ether (5×) and dried invacuo. The desired product 49 is isolated as a colorless solid (5.5%yield). ¹H NMR (400 MHz, CD₃OD): δ8.64 (s, 1H), 7.69 (s, 1H), 7.15 (t,²J_(H,F)=54 Hz, 1H), 4.82-4.76 (m, 1H), 4.66-4.61 (m, 1H), 4.17 (dd,²J_(H,H)=12 Hz, ³J_(H,H)=4.1 Hz, 1H), 3.78 (dd, ²J_(H,H)=12 Hz,³J_(H,H)=1.5 Hz, 1H), 3.72-3.61 (m, 8H), 1.61 (d, ³J_(H,H)=6.6 Hz, 3H);¹⁹F NMR (376 MHz, CD₃OD): δ−121.4 (s, 1 F), −121.5 (s, 1 F); MS (MALDI):m/z=438.4 ([M+H]⁺).

Example 50:4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine(50)

According to general procedure 1, compound 50 is obtained from startingmaterials i40 and i68 in 52% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.90 (s, 1H), 7.82 (t, ²J_(H,F)=55 Hz, 1H), 6.87 (br s,2H), 6.76 (s, 1H), 4.55-4.51 (m, 1H), 4.34-4.14 (m, 3H), 4.12-4.25 (m,2H), 3.92-3.80 (m, 1H), 3.76-3.68 (m, 3H), 3.55-3.51 (m, 1H), 3.38 (m,1H), 3.20-3.13 (m, 1H), 2.68 (m, 1H), 1.78 (m, 1H), 1.20 (d,³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.0 (br s, 2 F);MS (MALDI): m/z=420.6 ([M+H]⁺).

Example 51:4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine(51)

According to general procedure 1, compound 51 is obtained from startingmaterials i41 and i68 in 36% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.99 (s, 1H), 7.89 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s,2H), 6.77 (s, 1H), 4.69 (m, 3H), 4.37 (m, 1H), 3.91-3.85 (m, 3H),3.75-3.53 (m, 4H), 3.42-3.35 (m, 1H), 3.22-3.15 (m, 1H), 3.12-3.08 (m,1H), 1.85 (m, 1H), 1.24 (d, ³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−116.0 (br s, 2 F); MS (MALDI): m/z=420.6 ([M+H]⁺).

Example 52:4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(52)

According to general procedure 1, compound 52 is obtained from startingmaterials i42 and i68 in 44% yield as a colorless solid (1:1 mixture ofrotamers). ¹H NMR (400 MHz, (CD₃)₂SO): δ8.89 (m, 1H), 7.77 (m, 1H), 6.84(br s, 2H), 6.76 (s, 1H), 5.02-4.97 (m, 1H), 4.68-4.66 (m, 2H), 4.31 (m,1H), 3.89-3.85 (m, 1H), 3.79-3.57 (m, 3H), 3.57-3.44 (m, 4H), 3.22 (m,1H), 1.90-1.83 (m, 2H), 1.21 (d, ³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.5 (br s, 2 F); MS (MALDI): m/z=420.2 ([M+H]⁺).

Example 53:4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(53)

According to general procedure 1, compound 53 is obtained from startingmaterials i43 and i68 in 53% yield as a colorless solid (1:1 mixture ofrotamers). ¹H NMR (400 MHz, (CD₃)₂SO): δ8.90 (m, 1H), 7.77 (m, 1H), 6.84(br s, 2H), 6.76 (s, 1H), 5.02-4.96 (m, 1H), 4.68-4.62 (m, 2H), 3.90 (m,1H), 3.80 (m, 1H), 3.70 (m, 2H), 3.57 (m, 2H), 3.45 (m, 3H), 3.20 (m,1H), 1.90-1.83 (m, 2H), 1.21 (d, ³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.0 (br s, 2 F); MS (MALDI): m/z=420.2 ([M+H]⁺).

Example 54:5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(54)

According to general procedure 1, compound 54 is obtained from startingmaterials i8 and i68 in 61% yield as a colorless solid. ¹H NMR (400 MHz,(CD₃)₂SO): δ8.87 (s, 1H), 7.77 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s, 2H),6.76 (s, 1H), 4.47 (m, 4H), 3.89-3.81 (m, 4H), 3.51-3.34 (m, 4H), 3.12(m, 2H), 1.71 (m, 4H), 0.86 (m, 6H). ¹⁹F NMR (376 MHz, (CD₃)₂SO):δ−115.0 (br s, 2 F); MS (MALDI): m/z=450.3 ([M+H]⁺).

Example 55:5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl(pyridin-2-amine(55)

According to general procedure 1, compound 55 is obtained from startingmaterials i9 and i68 in 59% yield as a colorless solid. ¹H NMR (400 MHz,(CD₃)₂SO): δ8.74 (s, 1H), 7.65 (t, ²J_(H,F)=55 Hz, 1H), 6.81 (br s, 2H),6.75 (s, 1H), 3.68 (m, 8H), 3.49 (m, 4H), 2.46-2.38 (m, 4H), 2.25-2.16(m, 4H), 1.72-1.66 (m, 4H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.5 (br s,2 F); MS (MALDI): m/z=474.3 ([M+H]⁺).

Example 56:5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl(pyridin-2-amine(56)

According to general procedure 1, compound 56 is obtained from startingmaterials i10 and i68 in 59% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.76 (t, ²J_(H,F)=55 Hz, 1H), 6.82 (br s,2H), 6.76 (s, 1H), 4.50 (m, 2H), 4.29 (m, 2H), 4.02-3.84 (m, 4H), 3.40(m, 4H), 3.08 (m, 2H), 2.34 (m, 2H), 1.02 (m, 6H), 0.77 (m, 6H); ¹⁹F NMR(376 MHz, (CD₃)₂SO): δ−115.0 (br s, 2 F); MS (MALDI): m/z=478.4([M+H]⁺).

Example 57:4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-methyl-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine(57)

According to general procedure 1, compound 57 is obtained from startingmaterials i44 and i68 in 45% yield as a colorless solid (1:1 mixture ofrotamers). ¹H NMR (400 MHz, (CD₃)₂SO): δ8.87 (m, 1H), 7.77 (m, 1H), 6.84(br s, 2H), 6.76 (s, 1H), 4.71-4.35 (m, 4H), 3.92 (m, 1H), 3.72 (m, 1H),3.56 (m, 1H), 3.42 (m, 1H), 3.23-3.18 (m, 4H), 1.24 (m, 3H); ¹⁹F NMR(376 MHz, (CD₃)₂SO): δ−69, −115.0 (br s, 2 F); MS (MALDI): m/z=435.1([M+H]⁺).

Example 58:4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine(58)

According to general procedure 1, compound 58 is obtained from startingmaterials i45 and i68 in 41% yield as a colorless solid (1:1 mixture ofrotamers). ¹H NMR (400 MHz, (CD₃)₂SO): δ8.87 (m, 1H), 8.07 (m, 1H), 7.77(m, 1H), 6.86 (br s, 2H), 6.76 (s, 1H), 4.65-4.77 (m, 1H), 4.36-4.01 (m,3H), 3.83 (m, 1H), 3.62 (m, 1H), 3.52 (m, 1H), 3.35 (m, 1H), 3.10 (m,1H), 1.18 (d, ³J_(H,H)=6.9 Hz, 3H); MS (MALDI): m/z=421.1 ([M+H]⁺).

Example 59:4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-(cyclopropylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-amine(59)

According to general procedure 1, compound 59 is obtained from startingmaterials i46 and i68 in 32% yield as a colorless solid (1:1 mixture ofrotamers). ¹H NMR (400 MHz, (CD₃)₂SO): δ8.89-8.84 (m, 1H), 8.12-7.37 (m,2H), 6.81-6.75 (m, 3H), 4.64 (m, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.72(m, 1H), 3.56 (m, 1H), 3.39 (m, 2H), 3.14 (m, 2H), 1.20 (d, ³J_(H,H)=6.9Hz, 3H), 1.04 (m, 1H), 0.42 (m, 2H), 0.22 (m, 2H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.0 (br s, 2 F); MS (MALDI): m/z=393.0 ([M+H]⁺).

Example 60:4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]pyridin-2-amine(60)

According to general procedure 1, compound 60 is obtained from startingmaterials i47 and i68 in 41% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.96 (s, 1H), 7.75 (t, ²J_(H,F)=55 Hz, 1H), 7.07 (br s,2H), 6.80 (s, 1H), 5.10-4.97 (m, 2H), 4.78-4.54 (m, 1H), 4.33 (m, 1H),3.91 (m, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 3.41 (m, 1H), 3.29 (m, 1H),1.27 (d, ³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−69, −115.0(br s, 2 F); MS (MALDI): m/z=422.3 ([M+H]⁺).

Example 61:5-[4-(2,2-difluoroethoxy)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(61)

According to general procedure 1, compound 61 is obtained from startingmaterials i48 and i68 in 60% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.95 (s, 1H), 7.89 (t, ²J_(H,F)=55 Hz, 1H), 7.04 (br s,2H), 6.80 (s, 1H), 6.37 (m, 1H), 4.68-4.53 (m, 3H), 4.25 (m, 1H), 3.90(m, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 3.41 (m, 1H), 3.25 (m, 1H), 1.26(d, ³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.0 (br s, 2F), −126; MS (MALDI): m/z=404.1 ([M+H]⁺).

Example 62:5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(62)

According to general procedure 1, compound 62 is obtained from startingmaterials i49 and i68 in 20% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.90 (s, 1H), 7.86 (t, ²J_(H,F)=55 Hz, 1H), 6.82 (br s,2H), 6.76 (s, 1H), 4.67 (m, 1H), 4.35 (m, 1H), 3.93-3.43 (m, 14H), 3.16(m, 1H), 2.99 (m, 2H), 1.21 (d, ³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.0 (br s, 2 F); MS (MALDI): m/z=435.2 ([M+H]⁺).

Example 63:5-[4-[(4aS,7aR)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(63)

According to general procedure 1, compound 63 is obtained from startingmaterials i50 and i68 in 25% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.92 (s, 1H), 7.88 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s,2H), 6.76 (s, 1H), 4.70 (m, 1H), 4.36-4.26 (m, 3H), 3.88 (m, 1H),3.79-3.53 (m, 12H), 3.41 (m, 1H), 3.09 (m, 1H), 1.21 (d, ³J_(H,H)=6.9Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.0 (br s, 2 F); MS (MALDI):m/z=451.2 ([M+H]⁺).

Example 64:4-(difluoromethyl)-5-[4-(4,4-difluoro-1-piperidyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(64)

According to general procedure 1, compound 64 is obtained from startingmaterials i51 and i68 in 61% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.88 (s, 1H), 7.74 (t, ²J_(H,F)=55 Hz, 1H), 6.85 (br s,2H), 6.77 (s, 1H), 4.70 (m, 1H), 4.32 (m, 1H), 3.99 (m, 5H), 3.72 (m,1H), 3.56 (m, 1H), 3.41 (m, 1H), 3.18 (m, 1H), 2.01 (m, 4H), 1.21 (d,³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−95.5, −115.0 (br s,2 F); MS (MALDI): m/z=442.0 ([M+H]⁺).

Example 65:4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1,3,5-triazin-2-yl]pyridin-2-amine(65)

According to general procedure 1, compound 65 is obtained from startingmaterials i52 and i68 in 49% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.86 (s, 1H), 7.75 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 4.65 (m, 1H), 4.35 (m, 5H), 3.87 (m, 1H), 3.70 (m,5H), 3.57 (m, 1H), 3.43 (m, 1H), 3.16 (m, 1H), 1.79 (m, 4H), 1.20 (d,³J_(H,H)=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.5 (br s, 2 F);MS (MALDI): m/z=449.3 ([M+H]⁺).

Example 66:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(66)

According to general procedure 1, compound 66 is obtained from startingmaterials i55 and i68 in 61% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.77 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 4.46 (m, 2H), 3.81-3.77 (m, 6H), 3.55 (m, 2H), 3.44(m, 2H), 1.49 (s, 6H), 1.28 (d, ³J_(H,H)=6.9 Hz, 6H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.0 (br s, 2 F); MS (MALDI): m/z=450.4 ([M+H]⁺).

Example 67:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(67)

According to general procedure 1, compound 67 is obtained from startingmaterials i56 and i68 in 37% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.84 (s, 1H), 7.89 (t, ²J_(H,F)=55 Hz, 1H), 6.85 (br s,2H), 6.76 (s, 1H), 4.60 (m, 1H), 4.31 (m, 1H), 3.92 (m, 2H), 3.83 (m,4H), 3.65 (m, 1H), 3.51-3.41 (m, 5H), 3.28 (s, 3H), 3.12 (m, 1H), 1.49(s, 3H), 1.48 (s, 3H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.5 (br s, 2 F);MS (MALDI): m/z=466.4 ([M+H]⁺).

Example 68: 68:[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol(68)

According to general procedure 1, compound 68 is obtained from startingmaterials i57 and i68 in 58% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.83 (s, 1H), 7.77 (m, 1H), 6.84 (br s, 2H), 6.76 (s,1H), 4.91 (m, 1H), 4.35 (m, 2H), 4.05 (m, 1H), 3.97-3.70 (m, 6H),3.54-3.38 (m, 5H), 3.12 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); ¹⁹F NMR(376 MHz, (CD₃)₂SO): δ−115.5 (br s, 2 F); MS (MALDI): m/z=453.2([M+H]⁺).

Example 69:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine(69)

According to general procedure 1, compound 69 is obtained from startingmaterials i54 and i68 in 57% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.83 (s, 1H), 7.69 (t, ²J_(H,F)=55 Hz, 1H), 6.85 (br s,2H), 6.76 (s, 1H), 4.47-4.37 (m, 2H), 4.01 (m, 4H), 3.80-3.71 (m, 8H),3.45 (m, 2H), 1.48 (s, 6H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.7 (br s,2 F); MS (MALDI): m/z=464.3 ([M+H]⁺).

Example 70:5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine(70)

According to general procedure 1, compound 70 is obtained from startingmaterials i58 and i68 in 12% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.82 (s, 1H), 7.72 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 3.82 (m, 4H), 3.71 (m, 4H), 3.44 (m, 2H), 2.58 (m,4H), 1.64 (m, 1H), 1.44 (s, 6H), 0.45 (m, 2H), 0.36 (m, 2H);

¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.4 (br s, 2 F); MS (MALDI): m/z=460.4([M+H]⁺).

Example 71:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine(71)

According to general procedure 1, compound 71 is obtained from startingmaterials i59 and i68 in 42% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.82 (s, 1H), 7.73 (t, ²J_(H,F)=55 Hz, 1H), 6.83 (br s,2H), 6.76 (s, 1H), 3.88-3.69 (m, 10H), 3.47-3.44 (m, 4H), 3.24 (m, 3H),2.52-2.45 (m, 4H), 1.44 (s, 6H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.4(br s, 2 F); MS (MALDI): m/z=478.4 ([M+H]⁺).

Example 72:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine(72)

According to general procedure 1, compound 72 is obtained from startingmaterials i60 and i68 in 41% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.86 (s, 1H), 7.73 (t, ²J_(H,F)=55 Hz, 1H), 7.02 (br s,2H), 6.78 (s, 1H), 5.62 (m, 1H), 4.90 (m, 2H), 4.63 (m, 2H), 3.85 (m,4H), 3.49 (m, 2H), 3.13 (s, 6H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.7(br s, 2 F); MS (MALDI): m/z=409.3 ([M+H]⁺).

Example 73:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine(73)

According to general procedure 1, compound 73 is obtained from startingmaterials i61 and i68 in 44% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.76 (t, ²J_(H,F)=55 Hz, 1H), 6.99 (br s,2H), 6.78 (s, 1H), 5.48 (m, 1H), 3.84-3.73 (m, 8H), 3.49 (m, 2H), 2.21(m, 1H), 2.05 (m, 1H), 1.52 (s, 3H). 1.51 (s, 3H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.7 (br s, 2 F); MS (MALDI): m/z=423.3 ([M+H]⁺).

Example 74:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine(74)

According to general procedure 1, compound 74 is obtained from startingmaterials i62 and i68 in 37% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.76 (t, ²J_(H,F)=55 Hz, 1H), 6.99 (br s,2H), 6.78 (s, 1H), 5.48 (m, 1H), 3.84-3.73 (m, 8H), 3.49 (m, 2H), 2.21(m, 1H), 2.05 (m, 1H), 1.52 (s, 3H). 1.51 (s, 3H); ¹⁹F NMR (376 MHz,(CD₃)₂SO): δ−115.6 (br s, 2 F); MS (MALDI): m/z=423.3 ([M+H]⁺).

Example 75:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine(75)

According to general procedure 1, compound 75 is obtained from startingmaterials i63 and i68 in 61% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.87 (s, 1H), 7.76 (t, ²J_(H,F)=55 Hz, 1H), 6.99 (br s,2H), 6.78 (s, 1H), 5.15 (m, 1H), 3.82 (m, 6H), 3.48 (m, 4H), 2.07-2.00(m, 2H), 1.74 (m, 2H), 1.51 (s, 6H); ¹⁹F NMR (376 MHz, (CD₃)₂SO):δ−115.7 (br s, 2 F); MS (MALDI): m/z=437.4 ([M+H]⁺).

Example 76:4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine(76)

According to general procedure 1, compound 76 is obtained from startingmaterials i64 and i68 in 56% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.83 (s, 1H), 7.68 (t, ²J_(H,F)=55 Hz, 1H), 6.88 (br s,2H), 6.77 (s, 1H), 4.19 (m, 4H), 3.83 (m, 4H), 3.47 (m, 2H), 3.22 (m,4H), 1.52 (s, 6H); ¹⁹F NMR (376 MHz, (CD₃)₂SO): δ−115.3 (br s, 2 F); MS(MALDI): m/z=470.2 ([M+H]⁺).

Example 77:[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol(77)

According to general procedure 1, compound 77 is obtained from startingmaterials i53 and i68 in 31% yield as a colorless solid. ¹H NMR (400MHz, (CD₃)₂SO): δ8.88 (s, 1H), 7.78 (t, ²J_(H,F)=55 Hz, 1H), 6.84 (br s,2H), 6.76 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 4.58-4.24 (m, 3H), 4.05(m, 1H), 3.90 (m, 2H), 3.72 (m, 2H), 3.59 (m, 1H), 3.51-3.36 (m, 4H),3.23-3.02 (m, 2H), 1.23 (d, ³J_(H,H)=6.9 Hz, 3H); MS (MALDI): m/z=438.3([M+H]⁺).

In-Cell Western Blot

A2058 cells are plated at 20,000 cells/well in a 96-well plate (PerkinElmer, Cat. No. 6005558) and 24 hours later treated with differentcompounds for 1 hour. For each compound 7 different concentrations areapplied on cells (5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.155 μM, 0.08 μMand 0.04 μM). Cells are fixed with 4% paraformaldehyde for 30 minutes atroom temperature, washed 2 times with 1% BSA in PBS, permeabilized with0.1% Triton X-100 in PBS/1% BSA for 30 minutes at room temperature andblocked with 5% goat serum in PBS/1% BSA/0.1% Triton X-100 for 30minutes at room temperature. Cells are stained with primary antibodyeither with rabbit anti-pPKB S473 (1:500; Cell Signaling Technology,Cat. No. 4058) combined with mouse anti-α-tubulin (1:2000; used fornormalization; Sigma, Cat. No. T9026) or with rabbit anti-pS6 S235/S236(1:500; Cell Signalling Technology, Cat. No. 4856) combined with mouseanti-α-tubulin (1:2000; used for normalization) over night at 4° C.After 3 times 5 minutes wash with PBS/1% BSA/0.1% triton cells aretreated with the secondary antibodies goat-anti-mouse IRDye680 (LICOR,Cat. No. 926-68070) and goat-anti-rabbit IRDye800 (LICOR, 926-32211)(each diluted 1:500 in PBS/1% BSA/0.1% triton) for 1 hour while shakingin the dark. Cells are washed 3 times 5 minutes with PBS/1% BSA/0.1%triton and plate scanned with the Odyssey Infrared Scanning system usingboth 700 and 800 nm channels. As control for 0% inhibition vehicle (0.2%DMSO) is added to cells. To correct for background staining in the dataanalysis wells are treated only with secondary antibodies.

For data analysis the mean background signal from channel 700 nm and 800nm are subtracted from each signal in channel 700 nm and 800 nm,respectively. The signals in each channel are normalized to the 0%inhibition and then signal ratio 800 nm over 700 nm is performed toobtain the values for either pPKB S473 or pS6 S235/S236 normalized toα-Tubulin.

IC₅₀ values of each compound are determined by plotting the normalizedpPBK S473 and pS6 S235/S236 signals, respectively, versus the compoundconcentrations (in logarithmic scale) and then by fitting a sigmoidaldose-response curve with variable slope to the data using GraphPad™Prism.

TABLE 1 Comparative biological activities

 

pPKB 108 149 S473 IC₅₀ [nM] pS6 196 340 S235/236 IC₅₀ [nM]

 

pPKB  34  64 S473 IC₅₀ [nM] pS6  80 650 S235/236 IC₅₀ [nM]

TABLE 2 Comparative biological activities

 

pPKB 155 255 S473 IC₅₀ [nM] pS6 215 433 S235/236 IC₅₀ [nM]

 

pPKB  59 118 S473 IC₅₀ [nM] pS6  97 224 S235/236 IC₅₀ [nM]

TABLE 3 Comparative biological activities

 

pPKB 74 196 S473 IC₅₀ [nM] pS6 68  90 S235/236 IC₅₀ [nM]

 

pPKB 35  91 S473 IC₅₀ [nM] pS6 72 164 S235/236 IC₅₀ [nM]

TABLE 4 Comparative biological activities

 

pPKB 208 302 S473 IC₅₀ [nM] pS6 515 743 S235/236 IC₅₀ [nM]

 

pPKB  43 116 S473 IC₅₀ [nM] pS6 150 416 S235/236 IC₅₀ [nM]

TABLE 5 Comparative biological activities

 

pPKB 207 263 S473 IC₅₀ [nM] pS6 184 277 S235/236 IC₅₀ [nM]

 

pPKB  90 194 S473 IC₅₀ [nM] pS6 149 384 S235/236 IC₅₀ [nM]

TABLE 6 Comparative biological activities

 

pPKB 243 555 S473 IC₅₀ [nM] pS6 256 665 S235/236 IC₅₀ [nM]

 

pPKB  78 175 S473 IC₅₀ [nM] pS6 147 370 S235/236 IC₅₀ [nM]

TABLE 7 Comparative biological activities

 

pPKB 146 311 S473 IC₅₀ [nM] pS6 250 559 S235/236 IC₅₀ [nM]

 

pPKB  57 343 S473 IC₅₀ [nM] pS6 216 996 S235/236 IC₅₀ [nM]

TABLE 8 Comparative biological activities

 

pPKB 303 452 S473 IC₅₀ [nM] pS6 294 553 S235/236 IC₅₀ [nM]

 

pPKB  87 193 S473 IC₅₀ [nM] pS6 191 617 S235/236 IC₅₀ [nM]

TABLE 9 Comparative biological activities

 

pPKB 614  883 S473 IC₅₀ [nM] pS6 766 1100 S235/236 IC₅₀ [nM]

 

pPKB  77  290 S473 IC₅₀ [nM] pS6 146 1027 S235/236 IC₅₀ [nM]

TABLE 10 Comparative biological activities

 

pPKB 285 564 S473 IC₅₀ [nM] pS6 230 562 S235/236 IC₅₀ [nM]

 

pPKB  84 340 S473 IC₅₀ [nM] pS6 167 740 S235/236 IC₅₀ [nM]

TABLE 11 Comparative biological activities

 

pPKB 146 248 S473 IC₅₀ [nM] pS6 124 228 S235/236 IC₅₀ [nM]

 

pPKB 100 191 S473 IC₅₀ [nM] pS6 387 535 S235/236 IC₅₀ [nM]

TABLE 12 Comparative biological activities

PKB 100  689 S473 IC50[nM] P110α 161 1864 IC50[nM]

TABLE 13 Results of in-cell Western Blot In-cell Western blot pPKB S473pS6 S235/S236 Compound IC₅₀ [nM] IC₅₀ [nM] 1 108 196 2 34 80 3 231 105 4178 135 5 85 135 6 155 215 7 59 97 8 74 68 9 35 72 10 138 93 11 61 96 12219 407 13 37 120 14 349.5 883 15 49 286 16 207 184 17 90 149 18 243 25619 78 147 20 146 250 21 57 216 22 57 216 23 285 230 24 84 167 25 303 29426 87 191 27 614 766 28 77 146 31 146 124 32 100 387 35 207 229 36 99153 37 533 268 38 219 79 39 106 47 40 252 160 41 436 261 42 54 45 43 383154 44 197 87 45 234 93 46 956 426 47 469 176 48 100 nd

The invention claimed is:
 1. A compound of formula (I),

wherein X¹, X² and X³ are N; Y is N or CH; R¹ and R² are independentlyof each other (i) a morpholinyl of formula (II)

wherein the arrow denotes the bond in formula (I); and wherein R³ and R⁴are independently of each other H, C₁-C₃alkyl optionally substitutedwith one or two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy,C₁-C₂alkoxyC₁-C₃alkyl, CN, or C(O)O—C₁-C₂alkyl; or R³ and R⁴ formtogether a bivalent residue selected from C₁-C₃alkylene optionallysubstituted with 1 to 4 F, —CH₂—O—CH₂—, —CH₂—NH—CH₂—, or any of thestructures

wherein the arrows denote the bonds in formula (II); (ii) phenyloptionally substituted with 1 to 3 R⁷, wherein R⁷ is independently ateach occurrence halogen, —OH, C₁-C₃alkyl optionally substituted with oneor two OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,C₃-C₆cycloalkyl, —NH₂, NHCH₃ or N(CH₃)₂; (iii) a 5- to 6-memberedheteroaryl ring W containing one to four heteroatoms independentlyselected from N, O and S, optionally substituted by 1 to 3 R⁸, whereinR⁸ is independently at each occurrence halogen, —OH, C₁-C₃alkyloptionally substituted with one or two OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ orN(CH₃)₂; (iv) a saturated 4- to 6-membered heterocyclic ring Zcontaining 1 to 3 heteroatoms independently selected from N, O and S,optionally substituted by 1 to 3 R⁹; wherein R⁹ is independently at eachoccurrence halogen, —OH, C₁-C₃alkyl optionally substituted with one ortwo OH, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl,C₃-C₆cycloalkyl, ═O, —NH₂, NHCH₃ or N(CH₃)₂; or two R⁹ substituents formtogether a bivalent residue —R¹⁰R¹¹ selected from C₁-C₃alkyleneoptionally substituted with 1 to 4 F, —CH₂—O—CH₂— or —O—CH₂CH₂—O—; (v)OR¹², wherein R¹² is C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy,C₃-C₆cycloalkyl, C₁-C₂alkyleneC₃-C₆cycloalkyl; Cycle-P orC₁-C₂alkyleneCycle-P, wherein Cycle-P represents a saturated 4- to6-membered heterocyclic ring containing 1 to 3 heteroatoms independentlyselected from N, O and S, optionally substituted by 1 to 3 R¹³, whereinR¹³ is independently at each occurrence halogen, —OH, C₁-C₃alkyloptionally substituted with one or two OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ orN(CH₃); Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5-to 6-membered heteroaryl ring containing one to four heteroatomsindependently selected from N, O and S, optionally substituted by 1 to 3R¹⁴, wherein R¹⁴ is independently at each occurrence halogen, —OH,C₁-C₃alkyl optionally substituted with one or two OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ orN(CH₃); or (vi) NR¹⁵R¹⁶; wherein R¹⁵ and R¹⁶ are independently of eachother H, C₁-C₃alkyl optionally substituted with one or two OH,C₁-C₂fluoroalkyl, C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃ alkyl; Cycle-P orC₁-C₂alkyleneCycle-P, wherein Cycle-P represents a saturated 4- to6-membered heterocyclic ring containing 1 to 3 heteroatoms independentlyselected from N, O and S, optionally substituted by 1 to 3 R¹³, whereinR¹³ is independently at each occurrence halogen, —OH, C₁-C₃alkyloptionally substituted with one or two OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ orN(CH₃); Cycle-Q or C₁-C₂alkyleneCycle-Q, wherein Cycle-Q represents 5-to 6-membered heteroaryl ring containing one to four heteroatomsindependently selected from N, O and S, optionally substituted by 1 to 3R¹⁴, wherein R¹⁴ is independently at each occurrence halogen, —OH,C₁-C₃alkyl optionally substituted with one or two OH, C₁-C₂fluoroalkyl,C₁-C₂alkoxy, C₁-C₂alkoxyC₁-C₃alkyl, C₃-C₆cycloalkyl, —NH₂, NHCH₃ orN(CH₃); with the proviso that at least one of R¹ and R² is a morpholinylof formula II; or a tautomer, solvate, or a pharmaceutically acceptablesalt thereof.
 2. The compound of formula (I) according to claim 1,wherein said R¹ and said R² are independently of each other (i) amorpholinyl of formula (II); (ii) said 5- to 6-membered heteroaryl ringW; (iii) said saturated 4- to 6-membered heterocyclic ring Z; (iv) saidOR¹²; or (v) said NR¹⁵R¹⁶.
 3. The compound of formula (I) according toclaim 1, wherein said R¹ and said R² are independently of each otherselected from


4. The compound of formula (I) according to claim 1, wherein R¹ and R²are independently of each other selected from


5. The compound of formula (I) according to claim 1, wherein R¹ and R²are independently of each other selected from


6. The compound of formula (I) according to claim 1, wherein saidcompound is selected from4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;5-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;(4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-methyl-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-(cyclopropylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4-(2,2-difluoroethoxy)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4-[(4aS,7aR)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-(4,4-difluoro-1-piperidyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;4-(difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4,6-bis(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-[4-(2-methoxyethyl)piperazin-1-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(1,1-dioxo-1,4-thiazinan-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;3-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]oxazolidin-2-one;5-(4-((1R,2R,4S,5S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-6-((2R,4S)-7-oxa-9-azatricyclo[3.3.1.0^(2,4)]nonan-9-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis(6,7-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4-(6-amino-3-pyridyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-[4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-pyridyl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-pyrazin-2-yl-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1,2,4-triazol-1-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-1,2,4-triazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;and4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2H-tetrazol-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine.7. The compound of formula (I) according to claim 1, wherein saidcompound is selected from the group consisting of4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;and(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;or a tautomer, solvate, or a pharmaceutically acceptable salt thereof.8. The compound of formula (I) according to claim 1, wherein saidcompound is selected from,4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;and(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;or a tautomer, solvate, or a pharmaceutically acceptable salt thereof.9. The compound of formula (I) according to claim 1, wherein saidcompound is selected from4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine;5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;and(4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one.10. The compound of formula (I) according to claim 1, wherein R¹ and R²are independently of each other a morpholinyl of formula (II).
 11. Thecompound of formula (I) according to claim 10, wherein R¹ is equal toR².
 12. The compound of formula (I) according to claim 10, wherein R¹ isnot equal to R².
 13. The compound of formula (I) according to claim 1,wherein R¹ and R² are independently of each other a morpholinyl offormula (II) and said 5- to 6-membered heteroaryl ring W.
 14. Thecompound of formula (I) according to claim 1, wherein R¹ and R² areindependently of each other a morpholinyl of formula (II) and saidsaturated 4- to 6-membered heterocyclic ring Z.
 15. The compound offormula (I) according to claim 1, wherein R¹ and R² are independently ofeach other a morpholinyl of formula (II) and said OR¹².
 16. The compoundof formula (I) according to claim 1, wherein R¹ and R² are independentlyof each other a morpholinyl of formula (II) and said NR¹⁵R¹⁶.
 17. Apharmaceutical composition comprising a compound of formula (I)according to claim 1 and a pharmaceutically acceptable carrier.
 18. Thecompound of formula (I) according to claim 1, wherein said compound is4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amineor a tautomer, solvate, or a pharmaceutically acceptable salt thereof.19. The compound of formula (I) according to claim 1, wherein saidcompound is5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine or a tautomer, solvate, or a pharmaceutically acceptable saltthereof.
 20. The compound of formula (I) according to claim 1, whereinsaid compound is(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amineor a tautomer, solvate, or a pharmaceutically acceptable salt thereof.21. The compound of formula (I) according to claim 1, wherein saidcompound is 4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine or a tautomer,solvate, or a pharmaceutically acceptable salt thereof.